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1.  Patient survival and tumor characteristics associated with CHEK2:p.I157T – findings from the Breast Cancer Association Consortium 
Background
P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.
Methods
We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models.
Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.
Results
P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.
Conclusions
Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0758-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0758-5
PMCID: PMC5048645  PMID: 27716369
Breast cancer; CHEK2; CHK2; I157T; 1100delC; Survival; Pathology; Gene expression
2.  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
3.  Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry 
Background
Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry.
Methods
We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk.
Results
We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15–3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively.
Conclusion
Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0786-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0786-1
PMCID: PMC5146840  PMID: 27931260
Breast cancer risk; Prediction model; Methodology for SNP data analysis; Statistical methods in genetics
5.  rs2735383, located at a microRNA binding site in the 3’UTR of NBS1, is not associated with breast cancer risk 
Liu, Jingjing | Lončar, Ivona | Collée, J. Margriet | Bolla, Manjeet K. | Dennis, Joe | Michailidou, Kyriaki | Wang, Qin | Andrulis, Irene L. | Barile, Monica | Beckmann, Matthias W. | Behrens, Sabine | Benitez, Javier | Blomqvist, Carl | Boeckx, Bram | Bogdanova, Natalia V. | Bojesen, Stig E. | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Broeks, Annegien | Burwinkel, Barbara | Chang-Claude, Jenny | Chen, Shou-Tung | Chenevix-Trench, Georgia | Cheng, Ching Y. | Choi, Ji-Yeob | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Cuk, Katarina | Czene, Kamila | Dörk, Thilo | dos-Santos-Silva, Isabel | Fasching, Peter A. | Figueroa, Jonine | Flyger, Henrik | García-Closas, Montserrat | Giles, Graham G. | Glendon, Gord | Goldberg, Mark S. | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hart, Steven N. | Hartman, Mikael | Hatse, Sigrid | Hopper, John L. | Ito, Hidemi | Jakubowska, Anna | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela N. | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lophatananon, Artitaya | Jan Lubinski,  | Mannermaa, Arto | Matsuo, Keitaro | Milne, Roger L. | Neuhausen, Susan L. | Nevanlinna, Heli | Orr, Nick | Perez, Jose I. A. | Peto, Julian | Putti, Thomas C. | Pylkäs, Katri | Radice, Paolo | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schneeweiss, Andreas | Shen, Chen-Yang | Shrubsole, Martha J. | Shu, Xiao-Ou | Simard, Jacques | Southey, Melissa C. | Swerdlow, Anthony | Teo, Soo H. | Tessier, Daniel C. | Thanasitthichai, Somchai | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-Chen | Vachon, Celine | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Zheng, Wei | Hall, Per | Dunning, Alison M. | Easton, Douglas F. | Hooning, Maartje J. | van den Ouweland, Ans M. W. | Martens, John W. M. | Hollestelle, Antoinette
Scientific Reports  2016;6:36874.
NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3′-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936–1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969–1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905–1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
doi:10.1038/srep36874
PMCID: PMC5109293  PMID: 27845421
6.  Five endometrial cancer risk loci identified through genome-wide association analysis 
Cheng, Timothy HT | Thompson, Deborah J | O’Mara, Tracy A | Painter, Jodie N | Glubb, Dylan M | Flach, Susanne | Lewis, Annabelle | French, Juliet D | Freeman-Mills, Luke | Church, David | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Webb, Penelope M | Attia, John | Holliday, Elizabeth G | McEvoy, Mark | Scott, Rodney J | Henders, Anjali K | Martin, Nicholas G | Montgomery, Grant W | Nyholt, Dale R | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Dennis, Joe | Fasching, Peter A | Beckmann, Matthias W | Hein, Alexander | Ekici, Arif B | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo | Amant, Frederic | Schrauwen, Stefanie | Zhao, Hui | Lambrechts, Diether | Depreeuw, Jeroen | Dowdy, Sean C | Goode, Ellen L | Fridley, Brooke L | Winham, Stacey J | Njølstad, Tormund S | Salvesen, Helga B | Trovik, Jone | Werner, Henrica MJ | Ashton, Katie | Otton, Geoffrey | Proietto, Tony | Liu, Tao | Mints, Miriam | Tham, Emma | Consortium, CHIBCHA | Jun Li, Mulin | Yip, Shun H | Wang, Junwen | Bolla, Manjeet K | Michailidou, Kyriaki | Wang, Qin | Tyrer, Jonathan P | Dunlop, Malcolm | Houlston, Richard | Palles, Claire | Hopper, John L | Peto, Julian | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Cunningham, Julie M | Pharoah, Paul D P | Dunning, Alison M | Edwards, Stacey L | Easton, Douglas F | Tomlinson, Ian | Spurdle, Amanda B
Nature genetics  2016;48(6):667-674.
We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1 near SIVA1). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
doi:10.1038/ng.3562
PMCID: PMC4907351  PMID: 27135401
7.  Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk 
Guo, Xingyi | Long, Jirong | Zeng, Chenjie | Michailidou, Kyriaki | Ghoussaini, Maya | Bolla, Manjeet K. | Wang, Qin | Milne, Roger L. | Shu, Xiao-Ou | Cai, Qiuyin | Beesley, Jonathan | Kar, Siddhartha P. | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Blot, William | Bogdanova, Natalia | Bojesen, Stig E. | Brauch, Hiltrud | Brenner, Hermann | Brinton, Louise | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Cai, Hui | Canisius, Sander | Chang-Claude, Jenny | Choi, Ji-Yeob | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Darabi, Hatef | Devilee, Peter | Droit, Arnaud | Dörk, Thilo | Fasching, Peter A. | Fletcher, Olivia | Flyger, Henrik | Fostira, Florentia | Gaborieau, Valerie | García-Closas, Montserrat | Giles, Graham G. | Grip, Mervi | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hartman, Mikael | Hollestelle, Antoinette | Hopper, John L. | Hsiung, Chia-Ni | Ito, Hidemi | Jakubowska, Anna | Johnson, Nichola | Kabisch, Maria | Kang, Daehee | Khan, Sofia | Knight, Julia A. | Kosma, Veli-Matti | Lambrechts, Diether | Marchand, Loic Le | Li, Jingmei | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Matsuo, Keitaro | McLean, Catriona A. | Meindl, Alfons | Muir, Kenneth | Neuhausen, Susan L. | Nevanlinna, Heli | Nord, Silje | Olson, Janet E. | Orr, Nick | Peterlongo, Paolo | Putti, Thomas Choudary | Rudolph, Anja | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Shen, Chen-Yang | Shi, Jiajun | Shrubsole, Martha J | Southey, Melissa C. | Swerdlow, Anthony | Teo, Soo Hwang | Thienpont, Bernard | Toland, Amanda Ewart | Tollenaar, Robert A.E.M. | Tomlinson, Ian P.M. | Truong, Thérèse | Tseng, Chiu-chen | van den Ouweland, Ans | Wen, Wanqing | Winqvist, Robert | Wu, Anna | Yip, Cheng Har | Zamora, M. Pilar | Zheng, Ying | Hall, Per | Pharoah, Paul D.P. | Simard, Jacques | Chenevix-Trench, Georgia | Dunning, Alison M. | Easton, Douglas F. | Zheng, Wei
Background
A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.
Methods
We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.
Results
Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 (conditional p = 2.51 × 10−4; OR = 1.04; 95% CI 1.02–1.07) and rs77928427 (p = 1.86 × 10−4; OR = 1.04; 95% CI 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.
Conclusion
Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.
Impact
Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
doi:10.1158/1055-9965.EPI-15-0363
PMCID: PMC4633342  PMID: 26354892
Breast Cancer; Genetics; GWAS; 4q24; TET2
8.  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
9.  No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing 
Easton, Douglas F | Lesueur, Fabienne | Decker, Brennan | Michailidou, Kyriaki | Li, Jun | Allen, Jamie | Luccarini, Craig | Pooley, Karen A | Shah, Mitul | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Ahmad, Jamil | Thompson, Ella R | Damiola, Francesca | Pertesi, Maroulio | Voegele, Catherine | Mebirouk, Noura | Robinot, Nivonirina | Durand, Geoffroy | Forey, Nathalie | Luben, Robert N | Ahmed, Shahana | Aittomäki, Kristiina | Anton-Culver, Hoda | Arndt, Volker | Baynes, Caroline | Beckman, Matthias W | Benitez, Javier | Van Den Berg, David | Blot, William J | Bogdanova, Natalia V | Bojesen, Stig E | Brenner, Hermann | Chang-Claude, Jenny | Chia, Kee Seng | Choi, Ji-Yeob | Conroy, Don M | Cox, Angela | Cross, Simon S | Czene, Kamila | Darabi, Hatef | Devilee, Peter | Eriksson, Mikael | Fasching, Peter A | Figueroa, Jonine | Flyger, Henrik | Fostira, Florentia | García-Closas, Montserrat | Giles, Graham G | Glendon, Gord | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A | Hall, Per | Hart, Steven N | Hartman, Mikael | Hooning, Maartje J | Hsiung, Chia-Ni | Ito, Hidemi | Jakubowska, Anna | James, Paul A | John, Esther M | Johnson, Nichola | Jones, Michael | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela | Lambrechts, Diether | Li, Na | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Meindl, Alfons | Mitchell, Gillian | Muir, Kenneth | Nevelsteen, Ines | van den Ouweland, Ans | Peterlongo, Paolo | Phuah, Sze Yee | Pylkäs, Katri | Rowley, Simone M | Sangrajrang, Suleeporn | Schmutzler, Rita K | Shen, Chen-Yang | Shu, Xiao-Ou | Southey, Melissa C | Surowy, Harald | Swerdlow, Anthony | Teo, Soo H | Tollenaar, Rob A E M | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Vachon, Celine | Verhoef, Senno | Wong-Brown, Michelle | Zheng, Wei | Zheng, Ying | Nevanlinna, Heli | Scott, Rodney J | Andrulis, Irene L | Wu, Anna H | Hopper, John L | Couch, Fergus J | Winqvist, Robert | Burwinkel, Barbara | Sawyer, Elinor J | Schmidt, Marjanka K | Rudolph, Anja | Dörk, Thilo | Brauch, Hiltrud | Hamann, Ute | Neuhausen, Susan L | Milne, Roger L | Fletcher, Olivia | Pharoah, Paul D P | Campbell, Ian G | Dunning, Alison M | Le Calvez-Kelm, Florence | Goldgar, David E | Tavtigian, Sean V | Chenevix-Trench, Georgia
Journal of medical genetics  2016;53(5):298-309.
Background
BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
Methods
We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
Results
The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
Conclusions
These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
doi:10.1136/jmedgenet-2015-103529
PMCID: PMC4938802  PMID: 26921362
10.  Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 
Dunning, Alison M | Michailidou, Kyriaki | Kuchenbaecker, Karoline B | Thompson, Deborah | French, Juliet D | Beesley, Jonathan | Healey, Catherine S | Kar, Siddhartha | Pooley, Karen A | Lopez-Knowles, Elena | Dicks, Ed | Barrowdale, Daniel | Sinnott-Armstrong, Nicholas A | Sallari, Richard C | Hillman, Kristine M | Kaufmann, Susanne | Sivakumaran, Haran | Marjaneh, Mahdi Moradi | Lee, Jason S | Hills, Margaret | Jarosz, Monika | Drury, Suzie | Canisius, Sander | Bolla, Manjeet K | Dennis, Joe | Wang, Qin | Hopper, John L | Southey, Melissa C | Broeks, Annegien | Schmidt, Marjanka K | Lophatananon, Artitaya | Muir, Kenneth | Beckmann, Matthias W | Fasching, Peter A | dos-Santos-Silva, Isabel | Peto, Julian | Sawyer, Elinor J | Tomlinson, Ian | Burwinkel, Barbara | Marme, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E | Flyger, Henrik | González-Neira, Anna | Perez, Jose I A | Anton-Culver, Hoda | Eunjung, Lee | Arndt, Volker | Brenner, Hermann | Meindl, Alfons | Schmutzler, Rita K | Brauch, Hiltrud | Hamann, Ute | Aittomäki, Kristiina | Blomqvist, Carl | Ito, Hidemi | Matsuo, Keitaro | Bogdanova, Natasha | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Kosma, Veli-Matti | Mannermaa, Arto | Tseng, Chiu-chen | Wu, Anna H | Lambrechts, Diether | Wildiers, Hans | Chang-Claude, Jenny | Rudolph, Anja | Peterlongo, Paolo | Radice, Paolo | Olson, Janet E | Giles, Graham G | Milne, Roger L | Haiman, Christopher A | Henderson, Brian E | Goldberg, Mark S | Teo, Soo H | Yip, Cheng Har | Nord, Silje | Borresen-Dale, Anne-Lise | Kristensen, Vessela | Long, Jirong | Zheng, Wei | Pylkäs, Katri | Winqvist, Robert | Andrulis, Irene L | Knight, Julia A | Devilee, Peter | Seynaeve, Caroline | Figueroa, Jonine | Sherman, Mark E | Czene, Kamila | Darabi, Hatef | Hollestelle, Antoinette | van den Ouweland, Ans M W | Humphreys, Keith | Gao, Yu-Tang | Shu, Xiao-Ou | Cox, Angela | Cross, Simon S | Blot, William | Cai, Qiuyin | Ghoussaini, Maya | Perkins, Barbara J | Shah, Mitul | Choi, Ji-Yeob | Kang, Daehee | Lee, Soo Chin | Hartman, Mikael | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Brennan, Paul | Sangrajrang, Suleeporn | Ambrosone, Christine B | Toland, Amanda E | Shen, Chen-Yang | Wu, Pei-Ei | Orr, Nick | Swerdlow, Anthony | McGuffog, Lesley | Healey, Sue | Lee, Andrew | Kapuscinski, Miroslav | John, Esther M | Terry, Mary Beth | Daly, Mary B | Goldgar, David E | Buys, Saundra S | Janavicius, Ramunas | Tihomirova, Laima | Tung, Nadine | Dorfling, Cecilia M | van Rensburg, Elizabeth J | Neuhausen, Susan L | Ejlertsen, Bent | Hansen, Thomas V O | Osorio, Ana | Benitez, Javier | Rando, Rachel | Weitzel, Jeffrey N | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Papi, Laura | Ottini, Laura | Konstantopoulou, Irene | Apostolou, Paraskevi | Garber, Judy | Rashid, Muhammad Usman | Frost, Debra | Izatt, Louise | Ellis, Steve | Godwin, Andrew K | Arnold, Norbert | Niederacher, Dieter | Rhiem, Kerstin | Bogdanova-Markov, Nadja | Sagne, Charlotte | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Sinilnikova, Olga M | Mazoyer, Sylvie | Isaacs, Claudine | Claes, Kathleen B M | De Leeneer, Kim | de la Hoya, Miguel | Caldes, Trinidad | Nevanlinna, Heli | Khan, Sofia | Mensenkamp, Arjen R | Hooning, Maartje J | Rookus, Matti A | Kwong, Ava | Olah, Edith | Diez, Orland | Brunet, Joan | Pujana, Miquel Angel | Gronwald, Jacek | Huzarski, Tomasz | Barkardottir, Rosa B | Laframboise, Rachel | Soucy, Penny | Montagna, Marco | Agata, Simona | Teixeira, Manuel R | Park, Sue Kyung | Lindor, Noralane | Couch, Fergus J | Tischkowitz, Marc | Foretova, Lenka | Vijai, Joseph | Offit, Kenneth | Singer, Christian F | Rappaport, Christine | Phelan, Catherine M | Greene, Mark H | Mai, Phuong L | Rennert, Gad | Imyanitov, Evgeny N | Hulick, Peter J | Phillips, Kelly-Anne | Piedmonte, Marion | Mulligan, Anna Marie | Glendon, Gord | Bojesen, Anders | Thomassen, Mads | Caligo, Maria A | Yoon, Sook-Yee | Friedman, Eitan | Laitman, Yael | Borg, Ake | von Wachenfeldt, Anna | Ehrencrona, Hans | Rantala, Johanna | Olopade, Olufunmilayo I | Ganz, Patricia A | Nussbaum, Robert L | Gayther, Simon A | Nathanson, Katherine L | Domchek, Susan M | Arun, Banu K | Mitchell, Gillian | Karlan, Beth Y | Lester, Jenny | Maskarinec, Gertraud | Woolcott, Christy | Scott, Christopher | Stone, Jennifer | Apicella, Carmel | Tamimi, Rulla | Luben, Robert | Khaw, Kay-Tee | Helland, Åslaug | Haakensen, Vilde | Dowsett, Mitch | Pharoah, Paul D P | Simard, Jacques | Hall, Per | García-Closas, Montserrat | Vachon, Celine | Chenevix-Trench, Georgia | Antoniou, Antonis C | Easton, Douglas F | Edwards, Stacey L
Nature genetics  2016;48(4):374-386.
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
doi:10.1038/ng.3521
PMCID: PMC4938803  PMID: 26928228
11.  Patients with a high polygenic risk of breast cancer do not have an increased risk of radiotherapy toxicity 
Purpose
It has been hypothesized that increased predisposition to breast cancer may correlate with radiosensitivity and thus increased risk of toxicity following breast irradiation. This study investigated the relationship between common breast cancer risk variants and radiotherapy toxicity.
Experimental Design
Single nucleotide polymorphism genotypes were determined in female breast cancer patients from the RAPPER (Radiogenomics: Assessment of Polymorphisms for Predicting the Effects of Radiotherapy) study using the Illumina CytoSNP12 genome-wide array. A further 15,582,449 genotypes were imputed using the 1000 Genomes Project reference panel. Patient (n=1160) polygenic risk scores were generated by summing risk-allele dosages, both un-weighted and weighted by published effect sizes for breast cancer risk. Regression models were used to test associations of individual variants and polygenic risk scores with acute and late toxicity phenotypes (telangiectasia, breast edema, photographically assessed shrinkage, induration, pigmentation, breast pain, breast sensitivity, overall toxicity).
Results
Genotypes of 90 confirmed breast cancer risk variants were accurately determined and polygenic risk scores were approximately normally distributed. Variant rs6964587 was associated with increased breast edema five years following radiotherapy (beta=0.22; 95% CI=(0.09-0.34); p-value=7 × 10−4). No other associations were found between individual variants or the un-weighted (p>0.17) or weighted (p>0.13) polygenic risk score and radiotherapy toxicity. This study had >87% power to detect an association between the polygenic risk score (relative risk>1.1) and toxicity.
Conclusions
Cancer patients with a high polygenic predisposition to breast cancer do not have an increased risk of radiotherapy toxicity up to five years following radiotherapy but individual variants may increase risk.
doi:10.1158/1078-0432.CCR-15-1080
PMCID: PMC4751620  PMID: 26510858
radiotherapy; toxicity; adverse effects; genetics; breast cancer
12.  Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs) 
Darabi, Hatef | Beesley, Jonathan | Droit, Arnaud | Kar, Siddhartha | Nord, Silje | Moradi Marjaneh, Mahdi | Soucy, Penny | Michailidou, Kyriaki | Ghoussaini, Maya | Fues Wahl, Hanna | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Alonso, M. Rosario | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Benitez, Javier | Bogdanova, Natalia V. | Bojesen, Stig E. | Brauch, Hiltrud | Brenner, Hermann | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Chang-Claude, Jenny | Choi, Ji-Yeob | Conroy, Don M. | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Devilee, Peter | Dörk, Thilo | Easton, Douglas F. | Fasching, Peter A. | Figueroa, Jonine | Fletcher, Olivia | Flyger, Henrik | Galle, Eva | García-Closas, Montserrat | Giles, Graham G. | Goldberg, Mark S. | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A. | Hallberg, Emily | Hamann, Ute | Hartman, Mikael | Hollestelle, Antoinette | Hopper, John L. | Ito, Hidemi | Jakubowska, Anna | Johnson, Nichola | Kang, Daehee | Khan, Sofia | Kosma, Veli-Matti | Kriege, Mieke | Kristensen, Vessela | Lambrechts, Diether | Le Marchand, Loic | Lee, Soo Chin | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Mayes, Rebecca | McKay, James | Meindl, Alfons | Milne, Roger L. | Muir, Kenneth | Neuhausen, Susan L. | Nevanlinna, Heli | Olswold, Curtis | Orr, Nick | Peterlongo, Paolo | Pita, Guillermo | Pylkäs, Katri | Rudolph, Anja | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Seynaeve, Caroline | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Southey, Melissa C. | Stram, Daniel O. | Surowy, Harald | Swerdlow, Anthony | Teo, Soo H. | Tessier, Daniel C. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Vachon, Celine M. | Vincent, Daniel | Winqvist, Robert | Wu, Anna H. | Wu, Pei-Ei | Yip, Cheng Har | Zheng, Wei | Pharoah, Paul D. P. | Hall, Per | Edwards, Stacey L. | Simard, Jacques | French, Juliet D. | Chenevix-Trench, Georgia | Dunning, Alison M.
Scientific Reports  2016;6:32512.
Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
doi:10.1038/srep32512
PMCID: PMC5013272  PMID: 27600471
13.  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
14.  Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus 
Horne, Hisani N. | Chung, Charles C. | Zhang, Han | Yu, Kai | Prokunina-Olsson, Ludmila | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Muir, Kenneth | Lophatananon, Artitaya | Fasching, Peter A. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marme, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Benitez, Javier | González-Neira, Anna | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Khan, Sofia | Matsuo, Keitaro | Iwata, Hiroji | Dörk, Thilo | Bogdanova, Natalia V. | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Chenevix-Trench, Georgia | Wu, Anna H. | ven den Berg, David | Smeets, Ann | Zhao, Hui | Chang-Claude, Jenny | Rudolph, Anja | Radice, Paolo | Barile, Monica | Couch, Fergus J. | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Marchand, Loic Le | Goldberg, Mark S. | Teo, Soo H. | Taib, Nur A. M. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Shrubsole, Martha | Winqvist, Robert | Jukkola-Vuorinen, Arja | Andrulis, Irene L. | Knight, Julia A. | Devilee, Peter | Seynaeve, Caroline | García-Closas, Montserrat | Czene, Kamila | Darabi, Hatef | Hollestelle, Antoinette | Martens, John W. M. | Li, Jingmei | Lu, Wei | Shu, Xiao-Ou | Cox, Angela | Cross, Simon S. | Blot, William | Cai, Qiuyin | Shah, Mitul | Luccarini, Craig | Baynes, Caroline | Harrington, Patricia | Kang, Daehee | Choi, Ji-Yeob | Hartman, Mikael | Chia, Kee Seng | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Sangrajrang, Suleeporn | Brennan, Paul | Slager, Susan | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hou, Ming-Feng | Swerdlow, Anthony | Orr, Nick | Simard, Jacques | Hall, Per | Pharoah, Paul D. P. | Easton, Douglas F. | Chanock, Stephen J. | Dunning, Alison M. | Figueroa, Jonine D.
PLoS ONE  2016;11(8):e0160316.
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
doi:10.1371/journal.pone.0160316
PMCID: PMC4996485  PMID: 27556229
15.  Comprehensive genetic assessment of the ESR1 locus identifies a risk region for endometrial cancer 
Endocrine-related cancer  2015;22(5):851-861.
Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1. Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3,633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6,607 EC cases and 37,925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P = 1.86 × 10−5), which was stronger for cancers of endometrioid subtype (P = 3.76 × 10−6). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1, and eQTL analysis found that rs79575945 was associated with expression of SYNE1, a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1, at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
doi:10.1530/ERC-15-0319
PMCID: PMC4559752  PMID: 26330482
Endometrial cancer; ESR1; single-nucleotide polymorphisms; fine-mapping analysis
16.  Germline TERT promoter mutations are rare in familial melanoma 
Familial Cancer  2015;15:139-144.
Germline CDKN2A mutations occur in 40 % of 3-or-more case melanoma families while mutations of CDK4, BAP1, and genes involved in telomere function (ACD, TERF2IP,POT1), have also been implicated in melanomagenesis. Mutation of the promoter of the telomerase reverse transcriptase (TERT) gene (c.−57 T>G variant) has been reported in one family. We tested for the TERT promoter variant in 675 multicase families wild-type for the known high penetrance familial melanoma genes, 1863 UK population-based melanoma cases and 529 controls. Germline lymphocyte telomere length was estimated in carriers. The c.−57 T>G TERT promoter variant was identified in one 7-case family with multiple primaries and early age of onset (earliest, 15 years) but not among population cases or controls. One family member had multiple primary melanomas, basal cell carcinomas and a bladder tumour. The blood leukocyte telomere length of a carrier was similar to wild-type cases. We provide evidence confirming that a rare promoter variant of TERT (c.−57 T>G) is associated with high penetrance, early onset melanoma and potentially other cancers, and explains <1 % of UK melanoma multicase families. The identification of POT1 and TERT germline mutations highlights the importance of telomere integrity in melanoma biology.
Electronic supplementary material
The online version of this article (doi:10.1007/s10689-015-9841-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s10689-015-9841-9
PMCID: PMC4698275  PMID: 26433962
Melanoma; Familial; Genetic; TERT; Mutation
17.  Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer 
EBioMedicine  2016;10:150-163.
Nearly 50% of cancer patients undergo radiotherapy. Late radiotherapy toxicity affects quality-of-life in long-term cancer survivors and risk of side-effects in a minority limits doses prescribed to the majority of patients. Development of a test predicting risk of toxicity could benefit many cancer patients. We aimed to meta-analyze individual level data from four genome-wide association studies from prostate cancer radiotherapy cohorts including 1564 men to identify genetic markers of toxicity. Prospectively assessed two-year toxicity endpoints (urinary frequency, decreased urine stream, rectal bleeding, overall toxicity) and single nucleotide polymorphism (SNP) associations were tested using multivariable regression, adjusting for clinical and patient-related risk factors. A fixed-effects meta-analysis identified two SNPs: rs17599026 on 5q31.2 with urinary frequency (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.08–4.69, p-value 4.16 × 10− 8) and rs7720298 on 5p15.2 with decreased urine stream (OR 2.71, 95% CI 1.90–3.86, p-value = 3.21 × 10− 8). These SNPs lie within genes that are expressed in tissues adversely affected by pelvic radiotherapy including bladder, kidney, rectum and small intestine. The results show that heterogeneous radiotherapy cohorts can be combined to identify new moderate-penetrance genetic variants associated with radiotherapy toxicity. The work provides a basis for larger collaborative efforts to identify enough variants for a future test involving polygenic risk profiling.
Highlights
•SNPs rs17599026 and rs7720298 increase risk of urinary toxicity following radiotherapy in prostate cancer patients.•Data from heterogeneous radiotherapy cohorts can be meta-analyzed to identify genetic variants associated with toxicity.•A SNP-based predictive assay could improve the therapeutic index of radiotherapy and aid in individualization of cancer treatment.
Risk of radiotherapy side-effects in a minority limits doses given to the majority. A test is needed to predict risks so treatments are personalized. Recent whole-genome studies in a few hundred patients found none or one genetic variant increasing side-effect risk. Larger studies are needed, but difficult because treatments differ between centers. Our study of > 1500 prostate cancer patients from four centers found two variants. The research shows combining heterogeneous radiotherapy datasets works and larger collaborative efforts identifying enough variants for a future test are worthwhile. As nearly 50% of cancer patients have radiotherapy, our work could benefit many people.
doi:10.1016/j.ebiom.2016.07.022
PMCID: PMC5036513  PMID: 27515689
SNP, single nucleotide polymorphism; GWAS, genome-wide association study; EBRT, external bean radiotherapy; BED, biologic effective dose; MAF, minor allele frequency; STAT, standardized total average toxicity; PCA, principle components analysis; TURP, transurethral resection of the prostate; LD, linkage disequilibrium; ENCODE, encyclopedia of DNA elements; eQTL, expression quantitative trait locus; GTEx, Genotype-Tissue Expression project; Radiogenomics; Genome-wide association study; Prostate cancer; Radiation toxicity; Cancer survivorship; Quality of life
18.  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
19.  RAD51B in Familial Breast Cancer 
Pelttari, Liisa M. | Khan, Sofia | Vuorela, Mikko | Kiiski, Johanna I. | Vilske, Sara | Nevanlinna, Viivi | Ranta, Salla | Schleutker, Johanna | Winqvist, Robert | Kallioniemi, Anne | Dörk, Thilo | Bogdanova, Natalia V. | Figueroa, Jonine | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Dunning, Alison M. | García-Closas, Montserrat | Bolla, Manjeet K. | Dennis, Joe | Michailidou, Kyriaki | Wang, Qin | Hopper, John L. | Southey, Melissa C. | Rosenberg, Efraim H. | Fasching, Peter A. | Beckmann, Matthias W. | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Surowy, Harald | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Benitez, Javier | González-Neira, Anna | Neuhausen, Susan L. | Anton-Culver, Hoda | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Brüning, Thomas | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Van Dyck, Laurien | Janssen, Hilde | Chang-Claude, Jenny | Rudolph, Anja | Radice, Paolo | Peterlongo, Paolo | Hallberg, Emily | Olson, Janet E. | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Dumont, Martine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | Devilee, Peter | Seynaeve, Caroline | Hooning, Maartje J. | Collée, Margriet | Cox, Angela | Cross, Simon S. | Shah, Mitul | Luben, Robert N. | Hamann, Ute | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Couch, Fergus J. | Yannoukakos, Drakoulis | Orr, Nick | Swerdlow, Anthony | Darabi, Hatef | Li, Jingmei | Czene, Kamila | Hall, Per | Easton, Douglas F. | Mattson, Johanna | Blomqvist, Carl | Aittomäki, Kristiina | Nevanlinna, Heli
PLoS ONE  2016;11(5):e0153788.
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
doi:10.1371/journal.pone.0153788
PMCID: PMC4858276  PMID: 27149063
20.  Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair 
Day, Felix R. | Ruth, Katherine S. | Thompson, Deborah J. | Lunetta, Kathryn L. | Pervjakova, Natalia | Chasman, Daniel I. | Stolk, Lisette | Finucane, Hilary K. | Sulem, Patrick | Bulik-Sullivan, Brendan | Esko, Tõnu | Johnson, Andrew D. | Elks, Cathy E. | Franceschini, Nora | He, Chunyan | Altmaier, Elisabeth | Brody, Jennifer A. | Franke, Lude L. | Huffman, Jennifer E. | Keller, Margaux F. | McArdle, Patrick F. | Nutile, Teresa | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Smith, Jennifer A. | Teumer, Alexander | Traglia, Michela | Vuckovic, Dragana | Yao, Jie | Zhao, Wei | Albrecht, Eva | Amin, Najaf | Corre, Tanguy | Hottenga, Jouke-Jan | Mangino, Massimo | Smith, Albert V. | Tanaka, Toshiko | Abecasis, Goncalo | Andrulis, Irene L. | Anton-Culver, Hoda | Antoniou, Antonis C. | Arndt, Volker | Arnold, Alice M. | Barbieri, Caterina | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bernstein, Leslie | Bielinski, Suzette J. | Blomqvist, Carl | Boerwinkle, Eric | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Borresen-Dale, Anne-Lise | Boutin, Thibaud S | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Campbell, Archie | Campbell, Harry | Chanock, Stephen J. | Chapman, J. Ross | Chen, Yii-Der Ida | Chenevix-Trench, Georgia | Couch, Fergus J. | Coviello, Andrea D. | Cox, Angela | Czene, Kamila | Darabi, Hatef | De Vivo, Immaculata | Demerath, Ellen W. | Dennis, Joe | Devilee, Peter | Dörk, Thilo | dos-Santos-Silva, Isabel | Dunning, Alison M. | Eicher, John D. | Fasching, Peter A. | Faul, Jessica D. | Figueroa, Jonine | Flesch-Janys, Dieter | Gandin, Ilaria | Garcia, Melissa E. | García-Closas, Montserrat | Giles, Graham G. | Girotto, Giorgia G. | Goldberg, Mark S. | González-Neira, Anna | Goodarzi, Mark O. | Grove, Megan L. | Gudbjartsson, Daniel F. | Guénel, Pascal | Guo, Xiuqing | Haiman, Christopher A. | Hall, Per | Hamann, Ute | Henderson, Brian E. | Hocking, Lynne J. | Hofman, Albert | Homuth, Georg | Hooning, Maartje J. | Hopper, John L. | Hu, Frank B. | Huang, Jinyan | Humphreys, Keith | Hunter, David J. | Jakubowska, Anna | Jones, Samuel E. | Kabisch, Maria | Karasik, David | Knight, Julia A. | Kolcic, Ivana | Kooperberg, Charles | Kosma, Veli-Matti | Kriebel, Jennifer | Kristensen, Vessela | Lambrechts, Diether | Langenberg, Claudia | Li, Jingmei | Li, Xin | Lindström, Sara | Liu, Yongmei | Luan, Jian’an | Lubinski, Jan | Mägi, Reedik | Mannermaa, Arto | Manz, Judith | Margolin, Sara | Marten, Jonathan | Martin, Nicholas G. | Masciullo, Corrado | Meindl, Alfons | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L. | Müller-Nurasyid, Martina | Nalls, Michael | Neale, Ben M. | Nevanlinna, Heli | Neven, Patrick | Newman, Anne B. | Nordestgaard, Børge G. | Olson, Janet E. | Padmanabhan, Sandosh | Peterlongo, Paolo | Peters, Ulrike | Petersmann, Astrid | Peto, Julian | Pharoah, Paul D.P. | Pirastu, Nicola N. | Pirie, Ailith | Pistis, Giorgio | Polasek, Ozren | Porteous, David | Psaty, Bruce M. | Pylkäs, Katri | Radice, Paolo | Raffel, Leslie J. | Rivadeneira, Fernando | Rudan, Igor | Rudolph, Anja | Ruggiero, Daniela | Sala, Cinzia F. | Sanna, Serena | Sawyer, Elinor J. | Schlessinger, David | Schmidt, Marjanka K. | Schmidt, Frank | Schmutzler, Rita K. | Schoemaker, Minouk J. | Scott, Robert A. | Seynaeve, Caroline M. | Simard, Jacques | Sorice, Rossella | Southey, Melissa C. | Stöckl, Doris | Strauch, Konstantin | Swerdlow, Anthony | Taylor, Kent D. | Thorsteinsdottir, Unnur | Toland, Amanda E. | Tomlinson, Ian | Truong, Thérèse | Tryggvadottir, Laufey | Turner, Stephen T. | Vozzi, Diego | Wang, Qin | Wellons, Melissa | Willemsen, Gonneke | Wilson, James F. | Winqvist, Robert | Wolffenbuttel, Bruce B.H.R. | Wright, Alan F. | Yannoukakos, Drakoulis | Zemunik, Tatijana | Zheng, Wei | Zygmunt, Marek | Bergmann, Sven | Boomsma, Dorret I. | Buring, Julie E. | Ferrucci, Luigi | Montgomery, Grant W. | Gudnason, Vilmundur | Spector, Tim D. | van Duijn, Cornelia M | Alizadeh, Behrooz Z. | Ciullo, Marina | Crisponi, Laura | Easton, Douglas F. | Gasparini, Paolo P. | Gieger, Christian | Harris, Tamara B. | Hayward, Caroline | Kardia, Sharon L.R. | Kraft, Peter | McKnight, Barbara | Metspalu, Andres | Morrison, Alanna C. | Reiner, Alex P. | Ridker, Paul M. | Rotter, Jerome I. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Weir, David R. | Yerges-Armstrong, Laura M. | Price, Alkes L. | Stefansson, Kari | Visser, Jenny A. | Ong, Ken K. | Chang-Claude, Jenny | Murabito, Joanne M. | Perry, John R.B. | Murray, Anna
Nature genetics  2015;47(11):1294-1303.
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.
doi:10.1038/ng.3412
PMCID: PMC4661791  PMID: 26414677
21.  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
22.  CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer 
Thompson, Deborah J | O’Mara, Tracy A | Glubb, Dylan M | Painter, Jodie N | Cheng, Timothy | Folkerd, Elizabeth | Doody, Deborah | Dennis, Joe | Webb, Penelope M | Gorman, Maggie | Martin, Lynn | Hodgson, Shirley | Michailidou, Kyriaki | Tyrer, Jonathan P | Maranian, Mel J | Hall, Per | Czene, Kamila | Darabi, Hatef | Li, Jingmei | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif B | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Zhao, Hui | Depreeuw, Jeroen | Schrauwen, Stefanie | Amant, Frederic | Goode, Ellen L | Fridley, Brooke L | Dowdy, Sean C | Winham, Stacey J | Salvesen, Helga B | Trovik, Jone | Njolstad, Tormund S | Werner, Henrica MJ | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Carvajal-Carmona, Luis | Tham, Emma | Liu, Tao | Mints, Miriam | Scott, Rodney J | McEvoy, Mark | Attia, John | Holliday, Elizabeth G | Montgomery, Grant W | Martin, Nicholas G | Nyholt, Dale R | Henders, Anjali K | Hopper, John L | Traficante, Nadia | Ruebner, Matthias | Swerdlow, Anthony J | Burwinkel, Barbara | Brenner, Hermann | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Lambrechts, Diether | Chang-Claude, Jenny | Couch, Fergus J | Giles, Graham G | Kristensen, Vessela N | Cox, Angela | Bolla, Manjeet K | Wang, Qin | Bojesen, Stig E | Shah, Mitul | Luben, Robert | Khaw, Kay-Tee | Pharoah, Paul DP | Dunning, Alison M | Tomlinson, Ian | Dowsett, Mitch | Easton, Douglas F | Spurdle, Amanda B
Endocrine-related cancer  2015;23(2):77-91.
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol concentrations. We analysed 2,937 SNPs in 6,608 endometrial cancer cases and 37,925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8×10−11). SNP rs727479 was also among those most strongly associated with circulating estradiol concentrations in 2,767 post-menopausal controls (P=7.4×10−8). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on estradiol concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by estradiol. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
doi:10.1530/ERC-15-0386
PMCID: PMC4697192  PMID: 26574572
Endometrial cancer; CYP19A1; estradiol
23.  An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors 
Rudolph, Anja | Milne, Roger L. | Truong, Thérèse | Knight, Julia A. | Seibold, Petra | Flesch-Janys, Dieter | Behrens, Sabine | Eilber, Ursula | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Munday, Hannah R. | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Olson, Janet | Vachon, Celine M. | Hallberg, Emily | Castelao, J. Esteban | Carracedo, Angel | Torres, Maria | Li, Jingmei | Humphreys, Keith | Cordina-Duverger, Emilie | Menegaux, Florence | Flyger, Henrik | Nordestgaard, Børge G. | Nielsen, Sune F. | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Engelhardt, Ellen G. | Broeks, Annegien | Rutgers, Emiel J. | Glendon, Gord | Mulligan, Anna Marie | Cross, Simon | Reed, Malcolm | Gonzalez-Neira, Anna | Perez, José Ignacio Arias | Provenzano, Elena | Apicella, Carmel | Southey, Melissa C. | Spurdle, Amanda | Investigators, kConFab | Group, AOCS | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | McLean, Catriona | Baglietto, Laura | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Brüning, Thomas | Hamann, Ute | Ko, Yon-Dschun | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Mannermaa, Arto | Swerdlow, Anthony | Giles, Graham G. | Brenner, Hermann | Fasching, Peter A. | Chenevix-Trench, Georgia | Hopper, John | Benítez, Javier | Cox, Angela | Andrulis, Irene L. | Lambrechts, Diether | Gago-Dominguez, Manuela | Couch, Fergus | Czene, Kamila | Bojesen, Stig E. | Easton, Doug F. | Schmidt, Marjanka K. | Guénel, Pascal | Hall, Per | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Chang-Claude, Jenny
A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC.
Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator.
Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4).
In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
doi:10.1002/ijc.29188
PMCID: PMC4289418  PMID: 25227710
gene-environment interaction; breast cancer; risk factor; genetic susceptibility
24.  STROGAR – STrengthening the Reporting Of Genetic Association studies in Radiogenomics 
Despite publication of numerous radiogenomics studies to date, positive single nucleotide polymorphism (SNP) associations have rarely been reproduced in independent validation studies. A major reason for these inconsistencies is a high number of false positive findings because no adjustments were made for multiple comparisons. It is also possible that some validation studies were false negatives due to methodological shortcomings or a failure to reproduce relevant details of the original study. Transparent reporting is needed to ensure these flaws do not hamper progress in radiogenomics. In response to the need for improving the quality of research in the area, the Radiogenomics Consortium produced an 18-item checklist for reporting radiogenomics studies. It is recognised that not all studies will have recorded all of the information included in the checklist. However, authors should report on all checklist items and acknowledge any missing information. Use of STROGAR guidelines will advance the field of radiogenomics by increasing the transparency and completeness of reporting.
doi:10.1016/j.radonc.2013.07.011
PMCID: PMC4786020  PMID: 23993398
Radiogenomics; Reporting guidelines; Normal tissue toxicity; Genetics
25.  Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma 
Law, Matthew H. | Bishop, D. Timothy | Lee, Jeffrey E. | Brossard, Myriam | Martin, Nicholas G. | Moses, Eric K. | Song, Fengju | Barrett, Jennifer H. | Kumar, Rajiv | Easton, Douglas F. | Pharoah, Paul D. P. | Swerdlow, Anthony J. | Kypreou, Katerina P. | Taylor, John C. | Harland, Mark | Randerson-Moor, Juliette | Akslen, Lars A. | Andresen, Per A. | Avril, Marie-Françoise | Azizi, Esther | Scarrà, Giovanna Bianchi | Brown, Kevin M. | Dȩbniak, Tadeusz | Duffy, David L. | Elder, David E. | Fang, Shenying | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M. | Goldstein, Alisa M. | Gruis, Nelleke A. | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Ingvar, Christian | Kanetsky, Peter A. | Chen, Wei V. | Landi, Maria Teresa | Lang, Julie | Lathrop, G. Mark | Lubiński, Jan | Mackie, Rona M. | Mann, Graham J. | Molven, Anders | Montgomery, Grant W. | Novaković, Srdjan | Olsson, Håkan | Puig, Susana | Puig-Butille, Joan Anton | Qureshi, Abrar A. | Radford-Smith, Graham L. | van der Stoep, Nienke | van Doorn, Remco | Whiteman, David C. | Craig, Jamie E. | Schadendorf, Dirk | Simms, Lisa A. | Burdon, Kathryn P. | Nyholt, Dale R. | Pooley, Karen A. | Orr, Nicholas | Stratigos, Alexander J. | Cust, Anne E. | Ward, Sarah V. | Hayward, Nicholas K. | Han, Jiali | Schulze, Hans-Joachim | Dunning, Alison M. | Bishop, Julia A. Newton | Demenais, Florence | Amos, Christopher I. | MacGregor, Stuart | Iles, Mark M.
Nature genetics  2015;47(9):987-995.
Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international two-stage meta-analysis of 11 genome-wide association studies (GWAS, five unpublished) of CMM and Stage two datasets, totaling 15,990 cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10−8) as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and eQTL data highlight candidate genes including one involved in telomere biology.
doi:10.1038/ng.3373
PMCID: PMC4557485  PMID: 26237428

Results 1-25 (142)