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1.  PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS 
Southey, Melissa C | Goldgar, David E | Winqvist, Robert | Pylkäs, Katri | Couch, Fergus | Tischkowitz, Marc | Foulkes, William D | Dennis, Joe | Michailidou, Kyriaki | van Rensburg, Elizabeth J | Heikkinen, Tuomas | Nevanlinna, Heli | Hopper, John L | Dörk, Thilo | Claes, Kathleen BM | Reis-Filho, Jorge | Teo, Zhi Ling | Radice, Paolo | Catucci, Irene | Peterlongo, Paolo | Tsimiklis, Helen | Odefrey, Fabrice A | Dowty, James G | Schmidt, Marjanka K | Broeks, Annegien | Hogervorst, Frans B | Verhoef, Senno | Carpenter, Jane | Clarke, Christine | Scott, Rodney J | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Yang, Rongxi | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Bojesen, Stig | Nielsen, Sune F | Flyger, Henrik | Benitez, Javier | Zamora, M Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan | Ziogas, Argyrios | Clarke, Christina A | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Spurdle, Amanda B | Wauters, Els | Smeets, Dominiek | Beuselinck, Benoit | Floris, Giuseppe | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Olson, Janet E | Vachon, Celine | Pankratz, Vernon S | McLean, Catriona | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Kristensen, Vessela | Alnæs, Grethe Grenaker | Zheng, Wei | Hunter, David J | Lindstrom, Sara | Hankinson, Susan E | Kraft, Peter | Andrulis, Irene | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Jukkola-Vuorinen, Arja | Grip, Mervi | Kauppila, Saila | Devilee, Peter | Tollenaar, Robert A E M | Seynaeve, Caroline | Hollestelle, Antoinette | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Eccles, Diana M | Rafiq, Sajjad | Tapper, William J | Gerty, Sue M | Hooning, Maartje J | Martens, John W M | Collée, J Margriet | Tilanus-Linthorst, Madeleine | Hall, Per | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Cox, Angela | Reed, Malcolm W R | Luccarini, Craig | Baynes, Caroline | Dunning, Alison M | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Simard, Jacques | Dumont, Martine | Soucy, Penny | Eeles, Rosalind | Muir, Kenneth | Wiklund, Fredrik | Gronberg, Henrik | Schleutker, Johanna | Nordestgaard, Børge G | Weischer, Maren | Travis, Ruth C | Neal, David | Donovan, Jenny L | Hamdy, Freddie C | Khaw, Kay-Tee | Stanford, Janet L | Blot, William J | Thibodeau, Stephen | Schaid, Daniel J | Kelley, Joseph L | Maier, Christiane | Kibel, Adam S | Cybulski, Cezary | Cannon-Albright, Lisa | Butterbach, Katja | Park, Jong | Kaneva, Radka | Batra, Jyotsna | Teixeira, Manuel R | Kote-Jarai, Zsofia | Al Olama, Ali Amin | Benlloch, Sara | Renner, Stefan P | Hartmann, Arndt | Hein, Alexander | Ruebner, Matthias | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Lambretchs, Sandrina | Doherty, Jennifer A | Rossing, Mary Anne | Nickels, Stefan | Eilber, Ursula | Wang-Gohrke, Shan | Odunsi, Kunle | Sucheston-Campbell, Lara E | Friel, Grace | Lurie, Galina | Killeen, Jeffrey L | Wilkens, Lynne R | Goodman, Marc T | Runnebaum, Ingo | Hillemanns, Peter A | Pelttari, Liisa M | Butzow, Ralf | Modugno, Francesmary | Edwards, Robert P | Ness, Roberta B | Moysich, Kirsten B | du Bois, Andreas | Heitz, Florian | Harter, Philipp | Kommoss, Stefan | Karlan, Beth Y | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjaer, Susanne Krüger | Høgdall, Estrid | Peissel, Bernard | Bonanni, Bernardo | Bernard, Loris | Goode, Ellen L | Fridley, Brooke L | Vierkant, Robert A | Cunningham, Julie M | Larson, Melissa C | Fogarty, Zachary C | Kalli, Kimberly R | Liang, Dong | Lu, Karen H | Hildebrandt, Michelle A T | Wu, Xifeng | Levine, Douglas A | Dao, Fanny | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S | Marks, Jeffrey R | Akushevich, Lucy | Cramer, Daniel W | Schildkraut, Joellen | Terry, Kathryn L | Poole, Elizabeth M | Stampfer, Meir | Tworoger, Shelley S | Bandera, Elisa V | Orlow, Irene | Olson, Sara H | Bjorge, Line | Salvesen, Helga B | van Altena, Anne M | Aben, Katja K H | Kiemeney, Lambertus A | Massuger, Leon F A G | Pejovic, Tanja | Bean, Yukie | Brooks-Wilson, Angela | Kelemen, Linda E | Cook, Linda S | Le, Nhu D | Górski, Bohdan | Gronwald, Jacek | Menkiszak, Janusz | Høgdall, Claus K | Lundvall, Lene | Nedergaard, Lotte | Engelholm, Svend Aage | Dicks, Ed | Tyrer, Jonathan | Campbell, Ian | McNeish, Iain | Paul, James | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S | Rothstein, Joseph H | McGuire, Valerie | Sieh, Weiva | Cai, Hui | Shu, Xiao-Ou | Teten, Rachel T | Sutphen, Rebecca | McLaughlin, John R | Narod, Steven A | Phelan, Catherine M | Monteiro, Alvaro N | Fenstermacher, David | Lin, Hui-Yi | Permuth, Jennifer B | Sellers, Thomas A | Chen, Y Ann | Tsai, Ya-Yu | Chen, Zhihua | Gentry-Maharaj, Aleksandra | Gayther, Simon A | Ramus, Susan J | Menon, Usha | Wu, Anna H | Pearce, Celeste L | Van Den Berg, David | Pike, Malcolm C | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul DP | Song, Honglin | Winship, Ingrid | Chenevix-Trench, Georgia | Giles, Graham G | Tavtigian, Sean V | Easton, Doug F | Milne, Roger L
Journal of medical genetics  2016;53(12):800-811.
Background
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
Methods
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
Results
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
Conclusions
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
doi:10.1136/jmedgenet-2016-103839
PMCID: PMC5200636  PMID: 27595995
2.  Common variants at the CHEK2 gene locus and risk of epithelial ovarian cancer 
Lawrenson, Kate | Iversen, Edwin S. | Tyrer, Jonathan | Weber, Rachel Palmieri | Concannon, Patrick | Hazelett, Dennis J. | Li, Qiyuan | Marks, Jeffrey R. | Berchuck, Andrew | Lee, Janet M. | Aben, Katja K.H. | Anton-Culver, Hoda | Antonenkova, Natalia | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chenevix-Trench, Georgia | Chen, Ann | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Plisiecka-Halasa, Joanna | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Jakubowska, Anna | Paul, James | Jensen, Allan | Karlan, Beth Y. | Kjaer, Susanne Kruger | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Cannioto, Rikki | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | Nevanlinna, Heli | McNeish, Iain | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Noor Azmi, Mat Adenan | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Budzilowska, Agnieszka | Sellers, Thomas A. | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Timorek, Agnieszka | Tworoger, Shelley S. | Nieuwenhuysen, Els Van | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Coetzee, Gerhard A. | Freedman, Matthew L. | Monteiro, Alvaro N.A. | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul D. | Gayther, Simon A. | Schildkraut, Joellen M.
Carcinogenesis  2015;36(11):1341-1353.
Summary
Associations with EOC for variants at CHEK2 were found with the strongest association for the CHEK2 SNP rs6005807 with serous EOC. Common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10–7). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r 2 with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11–1.24, P = 1.1×10−7). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10−8). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r 2 = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10-8). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.
doi:10.1093/carcin/bgv138
PMCID: PMC4635670  PMID: 26424751
3.  Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer 
Background:
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.
Methods:
Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes—BRIP1, BARD1, PALB2 and NBN—in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.
Results:
We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10–4 and 8 x 10–4, respectively), but no differences for BARD1 (P = .39), NBN1 (P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10–4). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10–4) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10–5). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7×10–7).
Conclusions:
Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.
doi:10.1093/jnci/djv214
PMCID: PMC4643629  PMID: 26315354
4.  Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization 
Zhang, Ben | Shu, Xiao-Ou | Delahanty, Ryan J. | Zeng, Chenjie | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Wen, Wanqing | Long, Jirong | Li, Chun | Dunning, Alison M. | Chang-Claude, Jenny | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | Floris, Giuseppe | Schmidt, Marjanka K. | Rookus, Matti A. | van den Hurk, Katja | de Kort, Wim L. A. M. | Couch, Fergus J. | Olson, Janet E. | Hallberg, Emily | Vachon, Celine | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Li, Jingmei | Humphreys, Keith | Brand, Judith | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Burwinkel, Barbara | Marme, Frederik | Yang, Rongxi | Surowy, Harald | Benitez, Javier | Zamora, M. Pilar | Perez, Jose I. A. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Chenevix-Trench, Georgia | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Marchand, Loic Le | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Martens, John W. M. | Tilanus-Linthorst, Madeleine M. A. | Collée, J. Margriet | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony J. | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Radice, Paolo | Bogdanova, Natalia | Antonenkova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubiński, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Hamann, Ute | Torres, Diana | Schmutzler, Rita K. | Neuhausen, Susan L. | Anton-Culver, Hoda | Kristensen, Vessela N. | Grenaker Alnæs, Grethe I. | Pierce, Brandon L. | Kraft, Peter | Peters, Ulrike | Lindstrom, Sara | Seminara, Daniela | Burgess, Stephen | Ahsan, Habibul | Whittemore, Alice S. | John, Esther M. | Gammon, Marilie D. | Malone, Kathleen E. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Pharoah, Paul D. P. | Simard, Jacques | Hall, Per | Hunter, David J. | Easton, Douglas F. | Zheng, Wei
Background:
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
Methods:
We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control subjects.
Results:
The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor–positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10–8.
Conclusions:
Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
doi:10.1093/jnci/djv219
PMCID: PMC4643630  PMID: 26296642
5.  Shared genetics underlying epidemiological association between endometriosis and ovarian cancer 
Lu, Yi | Cuellar-Partida, Gabriel | Painter, Jodie N. | Nyholt, Dale R. | Morris, Andrew P. | Fasching, Peter A. | Hein, Alexander | Burghaus, Stefanie | Beckmann, Matthias W. | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Vanderstichele, Adriaan | Doherty, Jennifer Anne | Rossing, Mary Anne | Wicklund, Kristine G. | Chang-Claude, Jenny | Eilber, Ursula | Rudolph, Anja | Wang-Gohrke, Shan | Goodman, Marc T. | Bogdanova, Natalia | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo B. | Antonenkova, Natalia | Butzow, Ralf | Leminen, Arto | Nevanlinna, Heli | Pelttari, Liisa M. | Edwards, Robert P. | Kelley, Joseph L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Cannioto, Rikki | Høgdall, Estrid | Jensen, Allan | Giles, Graham G. | Bruinsma, Fiona | Kjaer, Susanne K. | Hildebrandt, Michelle A.T. | Liang, Dong | Lu, Karen H. | Wu, Xifeng | Bisogna, Maria | Dao, Fanny | Levine, Douglas A. | Cramer, Daniel W. | Terry, Kathryn L. | Tworoger, Shelley S. | Missmer, Stacey | Bjorge, Line | Salvesen, Helga B. | Kopperud, Reidun K. | Bischof, Katharina | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Brooks-Wilson, Angela | Olson, Sara H. | McGuire, Valerie | Rothstein, Joseph H. | Sieh, Weiva | Whittemore, Alice S. | Cook, Linda S. | Le, Nhu D. | Gilks, C. Blake | Gronwald, Jacek | Jakubowska, Anna | Lubiński, Jan | Gawełko, Jan | Song, Honglin | Tyrer, Jonathan P. | Wentzensen, Nicolas | Brinton, Louise | Trabert, Britton | Lissowska, Jolanta | Mclaughlin, John R. | Narod, Steven A. | Phelan, Catherine | Anton-Culver, Hoda | Ziogas, Argyrios | Eccles, Diana | Gayther, Simon A. | Gentry-Maharaj, Aleksandra | Menon, Usha | Ramus, Susan J. | Wu, Anna H. | Dansonka-Mieszkowska, Agnieszka | Kupryjanczyk, Jolanta | Timorek, Agnieszka | Szafron, Lukasz | Cunningham, Julie M. | Fridley, Brooke L. | Winham, Stacey J. | Bandera, Elisa V. | Poole, Elizabeth M. | Morgan, Terry K. | Risch, Harvey A. | Goode, Ellen L. | Schildkraut, Joellen M. | Webb, Penelope M. | Pearce, Celeste L. | Berchuck, Andrew | Pharoah, Paul D.P. | Montgomery, Grant W. | Zondervan, Krina T. | Chenevix-Trench, Georgia | MacGregor, Stuart
Human Molecular Genetics  2015;24(20):5955-5964.
Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18–0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07–0.89 and 0.40, 95% CI = 0.05–0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11–0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.
doi:10.1093/hmg/ddv306
PMCID: PMC4581608  PMID: 26231222
6.  Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus 
Lawrenson, Kate | Kar, Siddhartha | McCue, Karen | Kuchenbaeker, Karoline | Michailidou, Kyriaki | Tyrer, Jonathan | Beesley, Jonathan | Ramus, Susan J. | Li, Qiyuan | Delgado, Melissa K. | Lee, Janet M. | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Bandera, Elisa V. | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Matthias W. | Benitez, Javier | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Blomqvist, Carl | Blot, William | Bogdanova, Natalia | Bojesen, Anders | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Bruinsma, Fiona | Brunet, Joan | Buhari, Shaik Ahmad | Burwinkel, Barbara | Butzow, Ralf | Buys, Saundra S. | Cai, Qiuyin | Caldes, Trinidad | Campbell, Ian | Canniotto, Rikki | Chang-Claude, Jenny | Chiquette, Jocelyne | Choi, Ji-Yeob | Claes, Kathleen B. M. | Cook, Linda S. | Cox, Angela | Cramer, Daniel W. | Cross, Simon S. | Cybulski, Cezary | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Dansonka-Mieszkowska, Agnieszka | Darabi, Hatef | Dennis, Joe | Devilee, Peter | Diez, Orland | Doherty, Jennifer A. | Domchek, Susan M. | Dorfling, Cecilia M. | Dörk, Thilo | Dumont, Martine | Ehrencrona, Hans | Ejlertsen, Bent | Ellis, Steve | Engel, Christoph | Lee, Eunjung | Evans, D. Gareth | Fasching, Peter A. | Feliubadalo, Lidia | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Foretova, Lenka | Fostira, Florentia | Foulkes, William D. | Fridley, Brooke L. | Friedman, Eitan | Frost, Debra | Gambino, Gaetana | Ganz, Patricia A. | Garber, Judy | García-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Ghoussaini, Maya | Giles, Graham G. | Glasspool, Rosalind | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Goode, Ellen L. | Goodman, Marc T. | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Haiman, Christopher A. | Hall, Per | Hallberg, Emily | Hamann, Ute | Hansen, Thomas V. O. | Harrington, Patricia A. | Hartman, Mikael | Hassan, Norhashimah | Healey, Sue | Heitz, Florian | Herzog, Josef | Høgdall, Estrid | Høgdall, Claus K. | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hopper, John L. | Hulick, Peter J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Ito, Hidemi | Jakubowska, Anna | Janavicius, Ramunas | Jensen, Allan | John, Esther M. | Johnson, Nichola | Kabisch, Maria | Kang, Daehee | Kapuscinski, Miroslav | Karlan, Beth Y. | Khan, Sofia | Kiemeney, Lambertus A. | Kjaer, Susanne Kruger | Knight, Julia A. | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kupryjanczyk, Jolanta | Kwong, Ava | de la Hoya, Miguel | Laitman, Yael | Lambrechts, Diether | Le, Nhu | De Leeneer, Kim | Lester, Jenny | Levine, Douglas A. | Li, Jingmei | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Loud, Jennifer T. | Lu, Karen | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Le Marchand, Loic | Margolin, Sara | Marme, Frederik | Massuger, Leon F. A. G. | Matsuo, Keitaro | Mazoyer, Sylvie | McGuffog, Lesley | McLean, Catriona | McNeish, Iain | Meindl, Alfons | Menon, Usha | Mensenkamp, Arjen R. | Milne, Roger L. | Montagna, Marco | Moysich, Kirsten B. | Muir, Kenneth | Mulligan, Anna Marie | Nathanson, Katherine L. | Ness, Roberta B. | Neuhausen, Susan L. | Nevanlinna, Heli | Nord, Silje | Nussbaum, Robert L. | Odunsi, Kunle | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Olswold, Curtis | O'Malley, David | Orlow, Irene | Orr, Nick | Osorio, Ana | Park, Sue Kyung | Pearce, Celeste L. | Pejovic, Tanja | Peterlongo, Paolo | Pfeiler, Georg | Phelan, Catherine M. | Poole, Elizabeth M. | Pylkäs, Katri | Radice, Paolo | Rantala, Johanna | Rashid, Muhammad Usman | Rennert, Gad | Rhenius, Valerie | Rhiem, Kerstin | Risch, Harvey A. | Rodriguez, Gus | Rossing, Mary Anne | Rudolph, Anja | Salvesen, Helga B. | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schildkraut, Joellen M. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Sellers, Thomas A. | Seynaeve, Caroline | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Sieh, Weiva | Singer, Christian F. | Sinilnikova, Olga M. | Slager, Susan | Song, Honglin | Soucy, Penny | Southey, Melissa C. | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Sutter, Christian | Swerdlow, Anthony | Tchatchou, Sandrine | Teixeira, Manuel R. | Teo, Soo H. | Terry, Kathryn L. | Terry, Mary Beth | Thomassen, Mads | Tibiletti, Maria Grazia | Tihomirova, Laima | Tognazzo, Silvia | Toland, Amanda Ewart | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-chen | Tung, Nadine | Tworoger, Shelley S. | Vachon, Celine | van den Ouweland, Ans M. W. | van Doorn, Helena C. | van Rensburg, Elizabeth J. | Van't Veer, Laura J. | Vanderstichele, Adriaan | Vergote, Ignace | Vijai, Joseph | Wang, Qin | Wang-Gohrke, Shan | Weitzel, Jeffrey N. | Wentzensen, Nicolas | Whittemore, Alice S. | Wildiers, Hans | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Yoon, Sook-Yee | Yu, Jyh-Cherng | Zheng, Wei | Zheng, Ying | Khanna, Kum Kum | Simard, Jacques | Monteiro, Alvaro N. | French, Juliet D. | Couch, Fergus J. | Freedman, Matthew L. | Easton, Douglas F. | Dunning, Alison M. | Pharoah, Paul D. | Edwards, Stacey L. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Gayther, Simon A.
Nature Communications  2016;7:12675.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
doi:10.1038/ncomms12675
PMCID: PMC5023955  PMID: 27601076
7.  Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent 
Guo, Yan | Warren Andersen, Shaneda | Shu, Xiao-Ou | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Garcia-Closas, Montserrat | Milne, Roger L. | Schmidt, Marjanka K. | Chang-Claude, Jenny | Dunning, Allison | Bojesen, Stig E. | Ahsan, Habibul | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bogdanova, Natalia V. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brand, Judith | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Casey, Graham | Chenevix-Trench, Georgia | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Devilee, Peter | Dörk, Thilo | Dumont, Martine | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Fostira, Florentia | Gammon, Marilie | Giles, Graham G. | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hooning, Maartje J. | Hopper, John L. | Jakubowska, Anna | Jasmine, Farzana | Jenkins, Mark | John, Esther M. | Johnson, Nichola | Jones, Michael E. | Kabisch, Maria | Kibriya, Muhammad | Knight, Julia A. | Koppert, Linetta B. | Kosma, Veli-Matti | Kristensen, Vessela | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lindblom, Annika | Luben, Robert | Lubinski, Jan | Malone, Kathi E. | Mannermaa, Arto | Margolin, Sara | Marme, Frederik | McLean, Catriona | Meijers-Heijboer, Hanne | Meindl, Alfons | Neuhausen, Susan L. | Nevanlinna, Heli | Neven, Patrick | Olson, Janet E. | Perez, Jose I. A. | Perkins, Barbara | Peterlongo, Paolo | Phillips, Kelly-Anne | Pylkäs, Katri | Rudolph, Anja | Santella, Regina | Sawyer, Elinor J. | Schmutzler, Rita K. | Seynaeve, Caroline | Shah, Mitul | Shrubsole, Martha J. | Southey, Melissa C. | Swerdlow, Anthony J. | Toland, Amanda E. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Ursin, Giske | Van Der Luijt, Rob B. | Verhoef, Senno | Whittemore, Alice S. | Winqvist, Robert | Zhao, Hui | Zhao, Shilin | Hall, Per | Simard, Jacques | Kraft, Peter | Pharoah, Paul | Hunter, David | Easton, Douglas F. | Zheng, Wei
PLoS Medicine  2016;13(8):e1002105.
Background
Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
Methods
We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
Results
In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10−8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
Conclusions
BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Using Mendelian randomization analysis, Wei Zheng and colleagues probe potentially causal associations between BMI and breast cancer risk in both pre- and postmenopausal women.
Author Summary
Why Was This Study Done?
Body mass index (BMI) has been linked to breast cancer risk in conventional population studies.
In these studies, high BMI is associated with reduced risk of breast cancer in premenopausal women but with increased risk in postmenopausal women. These changed risks may be caused by BMI or caused by environmental factors that are associated with BMI.
We sought to use a research tool from the genetics field to understand BMI’s causal role in breast cancer.
What Did the Researchers Do and Find?
We took advantage of previously identified genetic sequence variations that are associated with BMI in European populations and used these variants to predict BMI. These variants are set at birth and are not affected by environmental factors; thus, outcomes associated with high BMI as predicted by genetic variants are more likely to be caused by high BMI itself rather than by environmental factors that are associated with high BMI.
Using databases containing individual genetic sequences and breast cancer diagnoses in a European population, we tested whether genetically predicted BMI was associated with diagnosis of breast cancer in either pre- or postmenopausal women.
We found that genetically predicted high BMI was associated with decreased breast cancer risk, in both cancer databases. Unexpectedly, this was true for both pre- and postmenopausal women.
What Do These Findings Mean?
Our results from postmenopausal women contradict prior findings from population studies, which used measured, rather than genetically predicted, BMI.
BMI predicted using genetic variants identified to date may be more closely related to body weight in early life or midlife, which is negatively associated with risk of breast cancer. Measured high BMI later in life may be influenced by environmental factors that are associated with increased risk of breast cancer.
More research is needed on the interrelationship of genetic factors, environment, and BMI in the risk of breast cancer.
doi:10.1371/journal.pmed.1002105
PMCID: PMC4995025  PMID: 27551723
8.  The impact of body mass index on treatment outcomes for patients with low-intermediate risk prostate cancer 
BMC Cancer  2016;16:557.
Background
Little is known about the relationship between preoperative body mass index and need for adjuvant radiation therapy (RT) following radical prostatectomy. The goal of this study was to evaluate the utility of body mass index in predicting adverse clinical outcomes which require adjuvant RT among men with organ-confined prostate cancer (PCa).
Methods
We used a prospective cohort of 1,170 low-intermediate PCa risk men who underwent radical prostatectomy and evaluated the effect of body mass index on adverse pathologic features and freedom from biochemical failure (FFbF). Clinical and pathologic variables were compared across the body mass index groups using an analysis of variance model for continuous variables or χ2 for categorical variables. Factors related to adverse pathologic features were examined using logistic regression models. Time to biochemical recurrence was compared across the groups using a log-rank survivorship analysis. Multivariable analysis predicting biochemical recurrence was conducted with a Cox proportional hazards model.
Results
Patients with elevated body mass index (defined as body mass index ≥25 kg/m2) had greater extraprostatic extension (p = 0.004), and positive surgical margins (p = 0.01). Elevated body mass index did not correlate with preoperative risk groupings (p = 0.94). However, when compared with non-obese patients (body mass index <30 kg/m2), obese patients (body mass index ≥30 kg/m2) were much more likely to have higher rate of adverse pathologic features (p = 0.006). In patients with low- and intermediate- risk disease, obesity was strongly associated with rate of pathologic upgrading of tumors (p = 0.01 and p = 0.02), respectively. After controlling for known preoperative risk factors, body mass index was independently associated with ≥2 adverse pathologic features (p = 0.002), an indicator for adjuvant RT as well as FFbF (p = 0.001).
Conclusions
Body mass index of ≥30 kg/m2 is independently associated with adverse pathologic features, which is an indicator for additional RT, particularly in patients with low-intermediate risk disease. Future studies may determine if this select group of patients may be best treated with definitive RT to reduce toxicity from additional RT following radical prostatectomy. We propose including body mass index in clinical decision-making for appropriate treatment recommendation for patients with low-intermediate risk PCa.
doi:10.1186/s12885-016-2572-y
PMCID: PMC4966583  PMID: 27473687
Body mass index; Biochemical failure; Tumor pathology; Prostate cancer treatment
9.  Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus 
Zeng, Chenjie | Guo, Xingyi | Long, Jirong | Kuchenbaecker, Karoline B. | Droit, Arnaud | Michailidou, Kyriaki | Ghoussaini, Maya | Kar, Siddhartha | Freeman, Adam | Hopper, John L. | Milne, Roger L. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Agata, Simona | Ahmed, Shahana | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Antonenkova, Natalia N. | Arason, Adalgeir | Arndt, Volker | Arun, Banu K. | Arver, Brita | Bacot, Francois | Barrowdale, Daniel | Baynes, Caroline | Beeghly-Fadiel, Alicia | Benitez, Javier | Bermisheva, Marina | Blomqvist, Carl | Blot, William J. | Bogdanova, Natalia V. | Bojesen, Stig E. | Bonanni, Bernardo | Borresen-Dale, Anne-Lise | Brand, Judith S. | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Buys, Saundra S. | Cai, Qiuyin | Caldes, Trinidad | Campbell, Ian | Carpenter, Jane | Chang-Claude, Jenny | Choi, Ji-Yeob | Claes, Kathleen B. M. | Clarke, Christine | Cox, Angela | Cross, Simon S. | Czene, Kamila | Daly, Mary B. | de la Hoya, Miguel | De Leeneer, Kim | Devilee, Peter | Diez, Orland | Domchek, Susan M. | Doody, Michele | Dorfling, Cecilia M. | Dörk, Thilo | dos-Santos-Silva, Isabel | Dumont, Martine | Dwek, Miriam | Dworniczak, Bernd | Egan, Kathleen | Eilber, Ursula | Einbeigi, Zakaria | Ejlertsen, Bent | Ellis, Steve | Frost, Debra | Lalloo, Fiona | Fasching, Peter A. | Figueroa, Jonine | Flyger, Henrik | Friedlander, Michael | Friedman, Eitan | Gambino, Gaetana | Gao, Yu-Tang | Garber, Judy | García-Closas, Montserrat | Gehrig, Andrea | Damiola, Francesca | Lesueur, Fabienne | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Giles, Graham G. | Godwin, Andrew K. | Goldgar, David E. | González-Neira, Anna | Greene, Mark H. | Guénel, Pascal | Haeberle, Lothar | Haiman, Christopher A. | Hallberg, Emily | Hamann, Ute | Hansen, Thomas V. O. | Hart, Steven | Hartikainen, Jaana M. | Hartman, Mikael | Hassan, Norhashimah | Healey, Sue | Hogervorst, Frans B. L. | Verhoef, Senno | Hendricks, Carolyn B. | Hillemanns, Peter | Hollestelle, Antoinette | Hulick, Peter J. | Hunter, David J. | Imyanitov, Evgeny N. | Isaacs, Claudine | Ito, Hidemi | Jakubowska, Anna | Janavicius, Ramunas | Jaworska-Bieniek, Katarzyna | Jensen, Uffe Birk | John, Esther M. | Joly Beauparlant, Charles | Jones, Michael | Kabisch, Maria | Kang, Daehee | Karlan, Beth Y. | Kauppila, Saila | Kerin, Michael J. | Khan, Sofia | Khusnutdinova, Elza | Knight, Julia A. | Konstantopoulou, Irene | Kraft, Peter | Kwong, Ava | Laitman, Yael | Lambrechts, Diether | Lazaro, Conxi | Le Marchand, Loic | Lee, Chuen Neng | Lee, Min Hyuk | Lester, Jenny | Li, Jingmei | Liljegren, Annelie | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mai, Phuong L. | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Matsuo, Keitaro | McGuffog, Lesley | Meindl, Alfons | Menegaux, Florence | Montagna, Marco | Muir, Kenneth | Mulligan, Anna Marie | Nathanson, Katherine L. | Neuhausen, Susan L. | Nevanlinna, Heli | Newcomb, Polly A. | Nord, Silje | Nussbaum, Robert L. | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olswold, Curtis | Osorio, Ana | Papi, Laura | Park-Simon, Tjoung-Won | Paulsson-Karlsson, Ylva | Peeters, Stephanie | Peissel, Bernard | Peterlongo, Paolo | Peto, Julian | Pfeiler, Georg | Phelan, Catherine M. | Presneau, Nadege | Radice, Paolo | Rahman, Nazneen | Ramus, Susan J. | Rashid, Muhammad Usman | Rennert, Gad | Rhiem, Kerstin | Rudolph, Anja | Salani, Ritu | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K | Schmutzler, Rita K. | Schoemaker, Minouk J. | Schürmann, Peter | Seynaeve, Caroline | Shen, Chen-Yang | Shrubsole, Martha J. | Shu, Xiao-Ou | Sigurdson, Alice | Singer, Christian F. | Slager, Susan | Soucy, Penny | Southey, Melissa | Steinemann, Doris | Swerdlow, Anthony | Szabo, Csilla I. | Tchatchou, Sandrine | Teixeira, Manuel R. | Teo, Soo H. | Terry, Mary Beth | Tessier, Daniel C. | Teulé, Alex | Thomassen, Mads | Tihomirova, Laima | Tischkowitz, Marc | Toland, Amanda E. | Tung, Nadine | Turnbull, Clare | van den Ouweland, Ans M. W. | van Rensburg, Elizabeth J. | ven den Berg, David | Vijai, Joseph | Wang-Gohrke, Shan | Weitzel, Jeffrey N. | Whittemore, Alice S. | Winqvist, Robert | Wong, Tien Y. | Wu, Anna H. | Yannoukakos, Drakoulis | Yu, Jyh-Cherng | Pharoah, Paul D. P. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison M. | Simard, Jacques | Couch, Fergus J. | Antoniou, Antonis C. | Easton, Douglas F. | Zheng, Wei
Background
Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
Method
We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.
Results
Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.
Conclusion
This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0718-0
PMCID: PMC4962376  PMID: 27459855
Fine-scale mapping; Genetic risk factor; PTHLH; CCDC91; Breast cancer; BRAC1 mutation carriers
10.  Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study 
Lee, Alice W. | Tyrer, Jonathan P. | Doherty, Jennifer A. | Stram, Douglas A. | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Spiewankiewicz, Beata | Myers, Emily J. | Chenevix-Trench, Georgia | Fasching, Peter A. | Beckmann, Matthias W. | Ekici, Arif B. | Hein, Alexander | Vergote, Ignace | Van Nieuwenhuysen, Els | Lambrechts, Diether | Wicklund, Kristine G. | Eilber, Ursula | Wang-Gohrke, Shan | Chang-Claude, Jenny | Rudolph, Anja | Sucheston-Campbell, Lara | Odunsi, Kunle | Moysich, Kirsten B. | Shvetsov, Yurii B. | Thompson, Pamela J. | Goodman, Marc T. | Wilkens, Lynne R. | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo B. | Bogdanova, Natalia | Pelttari, Liisa M. | Nevanlinna, Heli | Leminen, Arto | Edwards, Robert P. | Kelley, Joseph L. | Harter, Philipp | Schwaab, Ira | Heitz, Florian | du Bois, Andreas | Orsulic, Sandra | Lester, Jenny | Walsh, Christine | Karlan, Beth Y. | Hogdall, Estrid | Kjaer, Susanne K. | Jensen, Allan | Vierkant, Robert A. | Cunningham, Julie M. | Goode, Ellen L. | Fridley, Brooke L. | Southey, Melissa C. | Giles, Graham G. | Bruinsma, Fiona | Wu, Xifeng | Hildebrandt, Michelle A.T. | Lu, Karen | Liang, Dong | Bisogna, Maria | Levine, Douglas A. | Weber, Rachel Palmieri | Schildkraut, Joellen M. | Iversen, Edwin S. | Berchuck, Andrew | Terry, Kathryn L. | Cramer, Daniel W. | Tworoger, Shelley S. | Poole, Elizabeth M. | Olson, Sara H. | Orlow, Irene | Bandera, Elisa V. | Bjorge, Line | Tangen, Ingvild L. | Salvesen, Helga B. | Krakstad, Camilla | Massuger, Leon F.A.G. | Kiemeney, Lambertus A. | Aben, Katja K.H. | van Altena, Anne M. | Bean, Yukie | Pejovic, Tanja | Kellar, Melissa | Le, Nhu D. | Cook, Linda S. | Kelemen, Linda E. | Brooks-Wilson, Angela | Lubinski, Jan | Gronwald, Jacek | Cybulski, Cezary | Jakubowska, Anna | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Yang, Hannah | Nedergaard, Lotte | Lundvall, Lene | Hogdall, Claus | Song, Honglin | Campbell, Ian G. | Eccles, Diana | Glasspool, Rosalind | Siddiqui, Nadeem | Carty, Karen | Paul, James | McNeish, Iain A. | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Whittemore, Alice S. | McLaughlin, John R. | Risch, Harvey A. | Phelan, Catherine M. | Anton-Culver, Hoda | Ziogas, Argyrios | Menon, Usha | Ramus, Susan J. | Gentry-Maharaj, Aleksandra | Harrington, Patricia | Pike, Malcolm C. | Modugno, Francesmary | Rossing, Mary Anne | Ness, Roberta B. | Pharoah, Paul D.P. | Stram, Daniel O. | Wu, Anna H. | Pearce, Celeste Leigh
Gynecologic oncology  2014;136(3):542-548.
Objective
Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.
Methods
Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.
Results
We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p = 0.045, mucinous), LHCGR (p = 0.046, high-grade serous), GNRH (p = 0.041, high-grade serous), and FSHB (p = 0.036, overall invasive). There was also suggestive evidence for INHA (p = 0.060, overall invasive).
Conclusions
Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.
doi:10.1016/j.ygyno.2014.12.017
PMCID: PMC4892108  PMID: 25528498
Ovarian cancer; Gene; Gonadotropins; Genetics; Polymorphisms; Genetic variation
11.  Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium 
Johnatty, Sharon E. | Tyrer, Jonathan P. | Kar, Siddhartha | Beesley, Jonathan | Lu, Yi | Gao, Bo | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Rossing, Mary Anne | Doherty, Jennifer A. | Chang-Claude, Jenny | Modugno, Francesmary | Ness, Roberta B. | Moysich, Kirsten B. | Levine, Douglas A. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Gronwald, Jacek | Lubiński, Jan | Jakubowska, Anna | Cybulski, Cezary | Brinton, Louise | Lissowska, Jolanta | Wentzensen, Nicolas | Song, Honglin | Rhenius, Valerie | Campbell, Ian | Eccles, Diana | Sieh, Weiva | Whittemore, Alice S. | McGuire, Valerie | Rothstein, Joseph H. | Sutphen, Rebecca | Anton-Culver, Hoda | Ziogas, Argyrios | Gayther, Simon A. | Gentry-Maharaj, Aleksandra | Menon, Usha | Ramus, Susan J. | Pearce, Celeste L | Pike, Malcolm C | Stram, Daniel O. | Wu, Anna H. | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K. | Spiewankiewicz, Beata | Goodman, Marc T. | Wilkens, Lynne R. | Carney, Michael E. | Thompson, Pamela J | Heitz, Florian | du Bois, Andreas | Schwaab, Ira | Harter, Philipp | Pisterer, Jacobus | Hillemanns, Peter | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Winham, Stacey J | Earp, Madalene | Larson, Melissa C. | Fogarty, Zachary C. | Høgdall, Estrid | Jensen, Allan | Kjaer, Susanne Kruger | Fridley, Brooke L. | Cunningham, Julie M. | Vierkant, Robert A. | Schildkraut, Joellen M. | Iversen, Edwin S. | Terry, Kathryn L. | Cramer, Daniel W. | Bandera, Elisa V. | Orlow, Irene | Pejovic, Tanja | Bean, Yukie | Høgdall, Claus | Lundvall, Lene | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Sellers, Thomas | Kennedy, Catherine | Chiew, Yoke-Eng | Berchuck, Andrew | MacGregor, Stuart | deFazio, Anna | Pharoah, Paul D.P. | Goode, Ellen L. | deFazio, Anna | Webb, Penelope M. | Chenevix-Trench, Georgia
Purpose
Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.
Experimental Design
We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent firstline treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients including patients from The Cancer Genome Atlas. Additionally we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.
Results
Five SNPs were significantly associated (p≤1.0×10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1 and RP11-284F21.8 respectively (p≤7.1×10−6). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6×10−3).
Conclusion
We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.
doi:10.1158/1078-0432.CCR-15-0632
PMCID: PMC4624261  PMID: 26152742
progression-free survival; overall survival; epithelial ovarian cancer; lncRNA; chemotherapy
12.  Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium 
Johnatty, Sharon E. | Tyrer, Jonathan P. | Kar, Siddhartha | Beesley, Jonathan | Lu, Yi | Gao, Bo | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Rossing, Mary Anne | Doherty, Jennifer A. | Chang-Claude, Jenny | Modugno, Francesmary | Ness, Roberta B. | Moysich, Kirsten B. | Levine, Douglas A. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Gronwald, Jacek | Lubiński, Jan | Jakubowska, Anna | Cybulski, Cezary | Brinton, Louise | Lissowska, Jolanta | Wentzensen, Nicolas | Song, Honglin | Rhenius, Valerie | Campbell, Ian | Eccles, Diana | Sieh, Weiva | Whittemore, Alice S. | McGuire, Valerie | Rothstein, Joseph H. | Sutphen, Rebecca | Anton-Culver, Hoda | Ziogas, Argyrios | Gayther, Simon A. | Gentry-Maharaj, Aleksandra | Menon, Usha | Ramus, Susan J. | Pearce, Celeste L | Pike, Malcolm C | Stram, Daniel O. | Wu, Anna H. | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K. | Spiewankiewicz, Beata | Goodman, Marc T. | Wilkens, Lynne R. | Carney, Michael E. | Thompson, Pamela J | Heitz, Florian | du Bois, Andreas | Schwaab, Ira | Harter, Philipp | Pisterer, Jacobus | Hillemanns, Peter | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Winham, Stacey J | Earp, Madalene | Larson, Melissa C. | Fogarty, Zachary C. | Høgdall, Estrid | Jensen, Allan | Kjaer, Susanne Kruger | Fridley, Brooke L. | Cunningham, Julie M. | Vierkant, Robert A. | Schildkraut, Joellen M. | Iversen, Edwin S. | Terry, Kathryn L. | Cramer, Daniel W. | Bandera, Elisa V. | Orlow, Irene | Pejovic, Tanja | Bean, Yukie | Høgdall, Claus | Lundvall, Lene | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Sellers, Thomas | Kennedy, Catherine | Chiew, Yoke-Eng | Berchuck, Andrew | MacGregor, Stuart | deFazio, Anna | Pharoah, Paul D.P. | Goode, Ellen L. | deFazio, Anna | Webb, Penelope M. | Chenevix-Trench, Georgia
Purpose
Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome.
Experimental Design
We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent firstline treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients including patients from The Cancer Genome Atlas. Additionally we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis.
Results
Five SNPs were significantly associated (p≤1.0x10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11–179A10.1, RP11–314O13.1 and RP11–284F21.8 respectively (p≤7.1x10−6). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11–284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10−3).
Conclusion
We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies.
doi:10.1158/1078-0432.CCR-15-0632
PMCID: PMC4624261  PMID: 26152742
progression-free survival; overall survival; epithelial ovarian cancer; lncRNA; chemotherapy
13.  Case-control study of mammographic density and breast cancer risk using processed digital mammograms 
Background
Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care.
Methods
We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use.
Results
Median intra-reader reproducibility was high with a Pearson’s r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm2 (18.22 cm2) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41–2.04) for PD, and 1.54 (1.34–1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91–2.45), 2.57 (1.54–4.30), 3.22 (1.91–5.43), 4.88 (2.78–8.55) for PD, and 1.00 (ref.), 1.43 (0.85–2.40), 2.53 (1.53–4.19), 2.85 (1.73–4.69), 3.48 (2.14–5.65) for DA.
Conclusions
PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research.
doi:10.1186/s13058-016-0715-3
PMCID: PMC4875652  PMID: 27209070
Breast cancer; Mammography; Mammographic density; Risk factors; Epidemiology
14.  Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer 
Couch, Fergus J. | Kuchenbaecker, Karoline B. | Michailidou, Kyriaki | Mendoza-Fandino, Gustavo A. | Nord, Silje | Lilyquist, Janna | Olswold, Curtis | Hallberg, Emily | Agata, Simona | Ahsan, Habibul | Aittomäki, Kristiina | Ambrosone, Christine | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Lars | Beckmann, Matthias W. | Benitez, Javier | Blank, Stephanie V. | Blomqvist, Carl | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Burwinkel, Barbara | Buys, Saundra S. | Caldes, Trinidad | Caligo, Maria A. | Canzian, Federico | Carpenter, Jane | Chang-Claude, Jenny | Chanock, Stephen J. | Chung, Wendy K. | Claes, Kathleen B. M. | Cox, Angela | Cross, Simon S. | Cunningham, Julie M. | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Darabi, Hatef | de la Hoya, Miguel | Devilee, Peter | Diez, Orland | Ding, Yuan C. | Dolcetti, Riccardo | Domchek, Susan M. | Dorfling, Cecilia M. | dos-Santos-Silva, Isabel | Dumont, Martine | Dunning, Alison M. | Eccles, Diana M. | Ehrencrona, Hans | Ekici, Arif B. | Eliassen, Heather | Ellis, Steve | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Försti, Asta | Fostira, Florentia | Foulkes, William D. | Friebel, Tara | Friedman, Eitan | Frost, Debra | Gabrielson, Marike | Gammon, Marilie D. | Ganz, Patricia A. | Gapstur, Susan M. | Garber, Judy | Gaudet, Mia M. | Gayther, Simon A. | Gerdes, Anne-Marie | Ghoussaini, Maya | Giles, Graham G. | Glendon, Gord | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Gunter, Marc | Haeberle, Lothar | Haiman, Christopher A. | Hamann, Ute | Hansen, Thomas V. O. | Hart, Steven | Healey, Sue | Heikkinen, Tuomas | Henderson, Brian E. | Herzog, Josef | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hooning, Maartje J. | Hoover, Robert N. | Hopper, John L. | Humphreys, Keith | Hunter, David J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Jakubowska, Anna | James, Paul | Janavicius, Ramunas | Jensen, Uffe Birk | John, Esther M. | Jones, Michael | Kabisch, Maria | Kar, Siddhartha | Karlan, Beth Y. | Khan, Sofia | Khaw, Kay-Tee | Kibriya, Muhammad G. | Knight, Julia A. | Ko, Yon-Dschun | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kwong, Ava | Laitman, Yael | Lambrechts, Diether | Lazaro, Conxi | Lee, Eunjung | Le Marchand, Loic | Lester, Jenny | Lindblom, Annika | Lindor, Noralane | Lindstrom, Sara | Liu, Jianjun | Long, Jirong | Lubinski, Jan | Mai, Phuong L. | Makalic, Enes | Malone, Kathleen E. | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Martens, John W. M. | McGuffog, Lesley | Meindl, Alfons | Miller, Austin | Milne, Roger L. | Miron, Penelope | Montagna, Marco | Mazoyer, Sylvie | Mulligan, Anna M. | Muranen, Taru A. | Nathanson, Katherine L. | Neuhausen, Susan L. | Nevanlinna, Heli | Nordestgaard, Børge G. | Nussbaum, Robert L. | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Osorio, Ana | Park, Sue K. | Peeters, Petra H. | Peissel, Bernard | Peterlongo, Paolo | Peto, Julian | Phelan, Catherine M. | Pilarski, Robert | Poppe, Bruce | Pylkäs, Katri | Radice, Paolo | Rahman, Nazneen | Rantala, Johanna | Rappaport, Christine | Rennert, Gad | Richardson, Andrea | Robson, Mark | Romieu, Isabelle | Rudolph, Anja | Rutgers, Emiel J. | Sanchez, Maria-Jose | Santella, Regina M. | Sawyer, Elinor J. | Schmidt, Daniel F. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Schumacher, Fredrick | Scott, Rodney | Senter, Leigha | Sharma, Priyanka | Simard, Jacques | Singer, Christian F. | Sinilnikova, Olga M. | Soucy, Penny | Southey, Melissa | Steinemann, Doris | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Swerdlow, Anthony | Szabo, Csilla I. | Tamimi, Rulla | Tapper, William | Teixeira, Manuel R. | Teo, Soo-Hwang | Terry, Mary B. | Thomassen, Mads | Thompson, Deborah | Tihomirova, Laima | Toland, Amanda E. | Tollenaar, Robert A. E. M. | Tomlinson, Ian | Truong, Thérèse | Tsimiklis, Helen | Teulé, Alex | Tumino, Rosario | Tung, Nadine | Turnbull, Clare | Ursin, Giski | van Deurzen, Carolien H. M. | van Rensburg, Elizabeth J. | Varon-Mateeva, Raymonda | Wang, Zhaoming | Wang-Gohrke, Shan | Weiderpass, Elisabete | Weitzel, Jeffrey N. | Whittemore, Alice | Wildiers, Hans | Winqvist, Robert | Yang, Xiaohong R. | Yannoukakos, Drakoulis | Yao, Song | Zamora, M Pilar | Zheng, Wei | Hall, Per | Kraft, Peter | Vachon, Celine | Slager, Susan | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Monteiro, Alvaro A. N. | García-Closas, Montserrat | Easton, Douglas F. | Antoniou, Antonis C.
Nature Communications  2016;7:11375.
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
doi:10.1038/ncomms11375
PMCID: PMC4853421  PMID: 27117709
15.  Network-based integration of GWAS and gene expression identifies a HOX-centric network associated with serous ovarian cancer risk 
Kar, Siddhartha P. | Tyrer, Jonathan P. | Li, Qiyuan | Lawrenson, Kate | Aben, Katja K.H. | Anton-Culver, Hoda | Antonenkova, Natalia | Chenevix-Trench, Georgia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Berchuck, Andrew | Bisogna, Maria | Bjørge, Line | Bogdanova, Natalia | Brinton, Louise | Brooks-Wilson, Angela | Butzow, Ralf | Campbell, Ian | Carty, Karen | Chang-Claude, Jenny | Chen, Yian Ann | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas F. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus K. | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Paul, James | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y | Kjaer, Susanne K. | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph | Kiemeney, Lambertus A. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Iain A. | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Pearce, Celeste Leigh | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston-Campbell, Lara E. | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tsai, Ya-Yu | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Sellers, Thomas A. | Monteiro, Alvaro N. A. | Freedman, Matthew L. | Gayther, Simon A. | Pharoah, Paul D. P.
Background
Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by co-expression may also be enriched for additional EOC risk associations.
Methods
We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly co-expressed with each selected TF gene in the unified microarray data set of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this data set were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).
Results
Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P<0.05 and FDR<0.05). These results were replicated (P<0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.
Conclusion
We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.
Impact
Network analysis integrating large, context-specific data sets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization.
doi:10.1158/1055-9965.EPI-14-1270
PMCID: PMC4592449  PMID: 26209509
ovarian cancer; network analysis; GWAS; gene expression; transcription factors
16.  Cis-eQTL Analysis And Functional Validation Of Candidate Susceptibility Genes For High-Grade Serous Ovarian Cancer 
Lawrenson, Kate | Li, Qiyuan | Kar, Siddhartha | Seo, Ji-Heui | Tyrer, Jonathan | Spindler, Tassja J. | Lee, Janet | Chen, Yibu | Karst, Alison | Drapkin, Ronny | Aben, Katja K.H. | Anton-Culver, Hoda | Antonenkova, Natalia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chenevix-Trench, Georgia | Chen, Anne | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | James, Paul | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y | Kjaer, Susanne Kruger | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | Nevanlinna, Heli | McNeish, Ian | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Azmi, Mat Adenan Noor | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Sellers, Thomas A. | Shu, Xiao-Ou | Shvetsov, Yurii B | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tsai, Ya-Yu | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Monteiro, Alvaro | Pharoah, Paul D. | Gayther, Simon A. | Freedman, Matthew L. | Bowtell, David | Webb, Penelope M. | deFazio, Anna
Nature communications  2015;6:8234.
Genome-wide association studies have reported eleven regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4×10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6×10−10 for risk variants (P<10−4) within 10kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
doi:10.1038/ncomms9234
PMCID: PMC4580986  PMID: 26391404
17.  Genome-wide significant risk associations for mucinous ovarian carcinoma 
Kelemen, Linda E. | Lawrenson, Kate | Tyrer, Jonathan | Li, Qiyuan | M. Lee, Janet | Seo, Ji-Heui | Phelan, Catherine M. | Beesley, Jonathan | Chen, Xiaoqin | Spindler, Tassja J. | Aben, Katja K.H. | Anton-Culver, Hoda | Antonenkova, Natalia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chen, Y. Ann | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Engelholm, Svend Aage | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Iain | Menon, Usha | Modugno, Francesmary | Moes-Sosnowska, Joanna | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Nevanlinna, Heli | Azmi, Mat Adenan Noor | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste Leigh | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wlodzimierz, Sawicki | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Sellers, Thomas A. | Freedman, Matthew L. | Chenevix-Trench, Georgia | Pharoah, Paul D. | Gayther, Simon A. | Berchuck, Andrew
Nature genetics  2015;47(8):888-897.
Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
doi:10.1038/ng.3336
PMCID: PMC4520768  PMID: 26075790
18.  Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC) 
Jim, Heather S.L. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Sieh, Weiva | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Vierkant, Robert A. | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Thomsen, Lotte | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Palmieri Weber, Rachel | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Schernhammer, Eva | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Amankwah, Ernest | Berchuck, Andrew | Schildkraut, Joellen M. | Kelemen, Linda E. | Ramus, Susan J. | Monteiro, Alvaro N.A. | Goode, Ellen L. | Narod, Steven A. | Gayther, Simon A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
PMCID: PMC4722961  PMID: 26807442
19.  Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk 
Amankwah, Ernest K. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chen, Zhihua | Chen, Y. Ann | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Jim, Heather | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Kelemen, Linda E. | Berchuck, Andrew | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N.A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Genetic epidemiology  2015;39(8):689-697.
Introduction
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population.
Methods
We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant.
Results
In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements.
Conclusion
These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
doi:10.1002/gepi.21921
PMCID: PMC4721602  PMID: 26399219
ovarian cancer; epithelial-mesenchymal transition; single nucleotide polymorphisms
20.  The Role of Genome Sequencing in Personalized Breast Cancer Prevention 
Background
There is uncertainty about the benefits of using genome-wide sequencing to implement personalized preventive strategies at the population level, with some projections suggesting little benefit. We used data for all currently known breast cancer susceptibility variants to assess the benefits and harms of targeting preventive efforts to a population subgroup at highest genomic risk of breast cancer.
Methods
We used the allele frequencies and effect sizes of 86 known breast cancer variants to estimate the population distribution of breast cancer risks and evaluate the strategy of targeting preventive efforts to those at highest risk. We compared the efficacy of this strategy to that of a “best-case” strategy based on a risk distribution estimated from breast cancer concordance in monozygous twins, and to strategies based on previously estimated risk distributions.
Results
Targeting those in the top 25% of the risk distribution would include approximately half of all future breast cancer cases, compared to 70% captured by the best-case strategy and 35% based on previously known variants. In addition, current evidence suggests that reducing exposure to modifiable nongenetic risk factors will have greatest benefit for those at highest genetic risk.
Conclusions
These estimates suggest that personalized breast cancer preventive strategies based on genome sequencing will bring greater gains in disease prevention than previously projected. Moreover these gains will increase with increased understanding of the genetic etiology of breast cancer.
Impact
These results support the feasibility of using genome-wide sequencing to target the women who would benefit from mammography screening.
doi:10.1158/1055-9965.EPI-14-0559
PMCID: PMC4221442  PMID: 25342391
Breast cancer; screening; prevention; genetic risk score; risk stratification
21.  Ovarian Cancer Rates After Hysterectomy With and Without Salpingo-oophorectomy 
Obstetrics and gynecology  2014;123(1):65-72.
Objective
To estimate ovarian and peritoneal cancer rates after hysterectomy with and without salpingo-oophorectomy for benign conditions.
Methods
All patients after hysterectomy for benign disease from 1988–2006 in Kaiser Permanente Northern California, an integrated health organization. Incidence rates per 100,000 person-years were calculated.
Results
Of 56,692 patients, the majority (54%) underwent hysterectomy with bilateral salpingo-oophorectomy (BSO); 7% had hysterectomy with unilateral salpingo-oophorectomy, and 39% had hysterectomy alone. There were 40 ovarian and eight peritoneal cancers diagnosed during follow-up. Median age at ovarian and peritoneal cancer diagnosis was 50 and 64 years, respectively. Age-standardized rates (per 100,000 person-years) of ovarian or peritoneal cancer were 26.7 (95%CI=16–37.5) for those with hysterectomy alone, 22.8 (95%CI=0.0–46.8) for hysterectomy and unilateral salpingo-oophorectomy, and 3.9 (95%CI=1.5–6.4) for hysterectomy and BSO. Rates of ovarian cancer were 26.2 (95%CI=15.5–37) for those with hysterectomy alone, 17.5 (95%CI=0.0–39.1) for hysterectomy and unilateral salpingo-oophorectomy, and 1.7 (95%CI=0.4–3) for those with hysterectomy and BSO. Compared to women undergoing hysterectomy alone, those also receiving an unilateral salpingo-oophorectomy had a hazard ratio (HR) for ovarian cancer of 0.58 (95%CI=0.18–1.9); those undergoing BSO had a HR of 0.12 (95%CI=0.05–0.28).
Conclusions
The removal of both ovaries decreases incidence of ovarian and peritoneal cancers. Removal of one ovary might also decrease the incidence of ovarian cancer but warrants further investigation.
doi:10.1097/AOG.0000000000000061
PMCID: PMC4624417  PMID: 24463665
22.  Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer 
Lawrenson, Kate | Li, Qiyuan | Kar, Siddhartha | Seo, Ji-Heui | Tyrer, Jonathan | Spindler, Tassja J. | Lee, Janet | Chen, Yibu | Karst, Alison | Drapkin, Ronny | Aben, Katja K. H. | Anton-Culver, Hoda | Antonenkova, Natalia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chenevix-Trench, Georgia | Chen, Anne | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A. T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | James, Paul | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kruger Kjaer, Susanne | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F. A. G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | Nevanlinna, Heli | McNeish, Ian | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Azmi, Mat Adenan Noor | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Sellers, Thomas A. | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Timorek, Agnieszka | Tsai, Ya-Yu | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Monteiro, Alvaro | Pharoah, Paul D. | Gayther, Simon A. | Freedman, Matthew L.
Nature Communications  2015;6:8234.
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
doi:10.1038/ncomms9234
PMCID: PMC4580986  PMID: 26391404
23.  Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer 
Michailidou, Kyriaki | Beesley, Jonathan | Lindstrom, Sara | Canisius, Sander | Dennis, Joe | Lush, Michael | Maranian, Mel J | Bolla, Manjeet K | Wang, Qin | Shah, Mitul | Perkins, Barbara J | Czene, Kamila | Eriksson, Mikael | Darabi, Hatef | Brand, Judith S | Bojesen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | Nielsen, Sune F | Rahman, Nazneen | Turnbull, Clare | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | dos-Santos-Silva, Isabel | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Eilber, Ursula | Behrens, Sabine | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Aaltonen, Kirsimari | Ahsan, Habibul | Kibriya, Muhammad G | Whittemore, Alice S | John, Esther M | Malone, Kathleen E | Gammon, Marilie D | Santella, Regina M | Ursin, Giske | Makalic, Enes | Schmidt, Daniel F | Casey, Graham | Hunter, David J | Gapstur, Susan M | Gaudet, Mia M | Diver, W Ryan | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian E | Le Marchand, Loic | Berg, Christine D | Chanock, Stephen | Figueroa, Jonine | Hoover, Robert N | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | van Limbergen, Erik | Schmidt, Marjanka K | Broeks, Annegien | Verhoef, Senno | Cornelissen, Sten | Couch, Fergus J | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A | van der Luijt, Rob B | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Guénel, Pascal | Truong, Thérèse | Mulot, Claire | Sanchez, Marie | Burwinkel, Barbara | Marme, Frederik | Surowy, Harald | Sohn, Christof | Wu, Anna H | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O | González-Neira, Anna | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Lindblom, Annika | Margolin, Sara | Teo, Soo Hwang | Yip, Cheng Har | Taib, Nur Aishah Mohd | TAN, Gie-Hooi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | Collée, J Margriet | Blot, William | Signorello, Lisa B | Cai, Qiuyin | Hopper, John L | Southey, Melissa C | Tsimiklis, Helen | Apicella, Carmel | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Kristensen, Vessela N | Nord, Silje | Alnaes, Grethe I Grenaker | Giles, Graham G | Milne, Roger L | McLean, Catriona | Canzian, Federico | Trichopoulos, Dmitrios | Peeters, Petra | Lund, Eiliv | Sund, Malin | Khaw, Kay-Tee | Gunter, Marc J | Palli, Domenico | Mortensen, Lotte Maxild | Dossus, Laure | Huerta, Jose-Maria | Meindl, Alfons | Schmutzler, Rita K | Sutter, Christian | Yang, Rongxi | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Chan, Ching Wan | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Haeberle, Lothar | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J | Swerdlow, Anthony J | Brinton, Louise | Garcia-Closas, Montserrat | Zheng, Wei | Halverson, Sandra L | Shrubsole, Martha | Long, Jirong | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Bogdanova, Natalia V | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Huzarski, Tomasz | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Kabisch, Maria | Torres, Diana | Neuhausen, Susan L | Anton-Culver, Hoda | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Healey, Catherine S | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Simard, Jacques | Pharoah, Paul PDP | Kraft, Peter | Dunning, Alison M | Chenevix-Trench, Georgia | Hall, Per | Easton, Douglas F
Nature genetics  2015;47(4):373-380.
Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.
doi:10.1038/ng.3242
PMCID: PMC4549775  PMID: 25751625
24.  Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk 
Kelemen, Linda E. | Terry, Kathryn L. | Goodman, Marc T. | Webb, Penelope M. | Bandera, Elisa V. | McGuire, Valerie | Rossing, Mary Anne | Wang, Qinggang | Dicks, Ed | Tyrer, Jonathan P. | Song, Honglin | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Timorek, Agnieszka | Menon, Usha | Gentry-Maharaj, Aleksandra | Gayther, Simon A. | Ramus, Susan J. | Narod, Steven A. | Risch, Harvey A. | McLaughlin, John R. | Siddiqui, Nadeem | Glasspool, Rosalind | Paul, James | Carty, Karen | Gronwald, Jacek | Lubiński, Jan | Jakubowska, Anna | Cybulski, Cezary | Kiemeney, Lambertus A. | Massuger, Leon F. A. G. | van Altena, Anne M. | Aben, Katja K. H. | Olson, Sara H. | Orlow, Irene | Cramer, Daniel W. | Levine, Douglas A. | Bisogna, Maria | Giles, Graham G. | Southey, Melissa C. | Bruinsma, Fiona | Kjær, Susanne Krüger | Høgdall, Estrid | Jensen, Allan | Høgdall, Claus K. | Lundvall, Lene | Engelholm, Svend-Aage | Heitz, Florian | du Bois, Andreas | Harter, Philipp | Schwaab, Ira | Butzow, Ralf | Nevanlinna, Heli | Pelttari, Liisa M. | Leminen, Arto | Thompson, Pamela J. | Lurie, Galina | Wilkens, Lynne R. | Lambrechts, Diether | Van Nieuwenhuysen, Els | Lambrechts, Sandrina | Vergote, Ignace | Beesley, Jonathan | Fasching, Peter A. | Beckmann, Matthias W. | Hein, Alexander | Ekici, Arif B. | Doherty, Jennifer A. | Wu, Anna H. | Pearce, Celeste L. | Pike, Malcolm C. | Stram, Daniel | Chang-Claude, Jenny | Rudolph, Anja | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo B. | Bogdanova, Natalia | Antonenkova, Natalia | Odunsi, Kunle | Edwards, Robert P. | Kelley, Joseph L. | Modugno, Francesmary | Ness, Roberta B. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Fridley, Brooke L. | Vierkant, Robert A. | Cunningham, Julie M. | Wu, Xifeng | Lu, Karen | Liang, Dong | Hildebrandt, Michelle A.T. | Weber, Rachel Palmieri | Iversen, Edwin S. | Tworoger, Shelley S. | Poole, Elizabeth M. | Salvesen, Helga B. | Krakstad, Camilla | Bjorge, Line | Tangen, Ingvild L. | Pejovic, Tanja | Bean, Yukie | Kellar, Melissa | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Garcia-Closas, Montserrat | Campbell, Ian G. | Eccles, Diana | Whittemore, Alice S. | Sieh, Weiva | Rothstein, Joseph H. | Anton-Culver, Hoda | Ziogas, Argyrios | Phelan, Catherine M. | Moysich, Kirsten B. | Goode, Ellen L. | Schildkraut, Joellen M. | Berchuck, Andrew | Pharoah, Paul D.P. | Sellers, Thomas A. | Brooks-Wilson, Angela | Cook, Linda S. | Le, Nhu D.
Molecular nutrition & food research  2014;58(10):2023-2035.
Scope
We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
Methods and Results
Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006).
Conclusions
Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
doi:10.1002/mnfr.201400068
PMCID: PMC4197821  PMID: 25066213
case-control; DPYD; folate; polymorphism; SHMT1
25.  Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer 
Purpose
To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis.
Experimental Design
We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model.
Results
The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at ·4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality.
Conclusions
BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
doi:10.1158/1078-0432.CCR-14-2497
PMCID: PMC4338615  PMID: 25398451
Ovarian cancer; Epithelial ovarian cancer; BRCA1 gene; BRCA2 gene; Survival

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