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1.  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
2.  Cis-eQTL Analysis And Functional Validation Of Candidate Susceptibility Genes For High-Grade Serous Ovarian Cancer 
Lawrenson, Kate | Li, Qiyuan | Kar, Siddhartha | Seo, Ji-Heui | Tyrer, Jonathan | Spindler, Tassja J. | Lee, Janet | Chen, Yibu | Karst, Alison | Drapkin, Ronny | Aben, Katja K.H. | Anton-Culver, Hoda | Antonenkova, Natalia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chenevix-Trench, Georgia | Chen, Anne | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | James, Paul | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y | Kjaer, Susanne Kruger | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | Nevanlinna, Heli | McNeish, Ian | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Azmi, Mat Adenan Noor | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Sellers, Thomas A. | Shu, Xiao-Ou | Shvetsov, Yurii B | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J | Timorek, Agnieszka | Tsai, Ya-Yu | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Monteiro, Alvaro | Pharoah, Paul D. | Gayther, Simon A. | Freedman, Matthew L. | Bowtell, David | Webb, Penelope M. | deFazio, Anna
Nature communications  2015;6:8234.
Genome-wide association studies have reported eleven regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4×10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6×10−10 for risk variants (P<10−4) within 10kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
doi:10.1038/ncomms9234
PMCID: PMC4580986  PMID: 26391404
3.  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
4.  Genetic predisposition to ductal carcinoma in situ of the breast 
Petridis, Christos | Brook, Mark N. | Shah, Vandna | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Levi, Dina | Papouli, Efterpi | Orr, Nick | Cox, Angela | Cross, Simon S. | dos-Santos-Silva, Isabel | Peto, Julian | Swerdlow, Anthony | Schoemaker, Minouk J. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Benitez, Javier | González-Neira, Anna | Tessier, Daniel C. | Vincent, Daniel | Li, Jingmei | Figueroa, Jonine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Soucy, Penny | Simard, Jacques | Milne, Roger L. | Giles, Graham G. | Margolin, Sara | Lindblom, Annika | Brüning, Thomas | Brauch, Hiltrud | Southey, Melissa C. | Hopper, John L. | Dörk, Thilo | Bogdanova, Natalia V. | Kabisch, Maria | Hamann, Ute | Schmutzler, Rita K. | Meindl, Alfons | Brenner, Hermann | Arndt, Volker | Winqvist, Robert | Pylkäs, Katri | Fasching, Peter A. | Beckmann, Matthias W. | Lubinski, Jan | Jakubowska, Anna | Mulligan, Anna Marie | Andrulis, Irene L. | Tollenaar, Rob A. E. M. | Devilee, Peter | Le Marchand, Loic | Haiman, Christopher A. | Mannermaa, Arto | Kosma, Veli-Matti | Radice, Paolo | Peterlongo, Paolo | Marme, Frederik | Burwinkel, Barbara | van Deurzen, Carolien H. M. | Hollestelle, Antoinette | Miller, Nicola | Kerin, Michael J. | Lambrechts, Diether | Floris, Giuseppe | Wesseling, Jelle | Flyger, Henrik | Bojesen, Stig E. | Yao, Song | Ambrosone, Christine B. | Chenevix-Trench, Georgia | Truong, Thérèse | Guénel, Pascal | Rudolph, Anja | Chang-Claude, Jenny | Nevanlinna, Heli | Blomqvist, Carl | Czene, Kamila | Brand, Judith S. | Olson, Janet E. | Couch, Fergus J. | Dunning, Alison M. | Hall, Per | Easton, Douglas F. | Pharoah, Paul D. P. | Pinder, Sarah E. | Schmidt, Marjanka K | Tomlinson, Ian | Roylance, Rebecca | García-Closas, Montserrat | Sawyer, Elinor J.
Background
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.
Methods
To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.
Results
Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing.
Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC.
We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8.
Conclusion
In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0675-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0675-7
PMCID: PMC4756509  PMID: 26884359
Ductal carcinoma in situ; Association study; Genetic predisposition; Common variants
5.  Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer 
Kabisch, Maria | Lorenzo Bermejo, Justo | Dünnebier, Thomas | Ying, Shibo | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | 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 | Peeters, Stephanie | Weltens, Caroline | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Purrington, Kristen | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Johnson, Nichola | Fletcher, Olivia | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Hogervorst, Frans B.L. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Burwinkel, Barbara | Marmé, Frederik | Yang, Rongxi | Bugert, Peter | González-Neira, Anna | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose I. | 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 | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Kriege, Mieke | Koppert, Linetta B. | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slettedahl, Seth | Toland, Amanda E. | Vachon, Celine | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Ruebner, Matthias | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Swerdlow, Anthony | García-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Radice, Paolo | Peterlongo, Paolo | Scuvera, Giulietta | Fortuzzi, Stefano | Bogdanova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Zheng, Wei | Shrubsole, Martha J. | Cai, Qiuyin | Torres, Diana | Anton-Culver, Hoda | Kristensen, Vessela | Bacot, François | Tessier, Daniel C. | Vincent, Daniel | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Simard, Jacques | Chenevix-Trench, Georgia | Hall, Per | Pharoah, Paul D.P. | Dunning, Alison M. | Easton, Douglas F. | Hamann, Ute
Carcinogenesis  2015;36(2):256-271.
Summary
This is the first study investigating the contribution of inherited variants in core genes of the chromosomal passenger complex to breast cancer susceptibility. It was found that several INCENP variants are associated with the risk of ER-negative breast cancer in the European population.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
doi:10.1093/carcin/bgu326
PMCID: PMC4335262  PMID: 25586992
6.  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 M J | 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 D P | Dunning, Alison M | Tomlinson, Ian | Dowsett, Mitch | Easton, Douglas F | Spurdle, Amanda B
Endocrine-Related Cancer  2016;23(2):77-91.
Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 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 E2 concentrations in 2767 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 E2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. 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
7.  DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer 
Nature Communications  2016;7:10478.
Identifying molecular alterations in normal tissue adjacent to cancer is important for understanding cancer aetiology and designing preventive measures. Here we analyse the DNA methylome of 569 breast tissue samples, including 50 from cancer-free women and 84 from matched normal cancer pairs. We use statistical algorithms for dissecting intra- and inter-sample cellular heterogeneity and demonstrate that normal tissue adjacent to breast cancer is characterized by tens to thousands of epigenetic alterations. We show that their genomic distribution is non-random, being strongly enriched for binding sites of transcription factors specifying chromatin architecture. We validate the field defects in an independent cohort and demonstrate that over 30% of the alterations exhibit increased enrichment within matched cancer samples. Breast cancers highly enriched for epigenetic field defects, exhibit adverse clinical outcome. Our data support a model where clonal epigenetic reprogramming towards reduced differentiation in normal tissue is an important step in breast carcinogenesis.
Altered epigenetics is a feature of cancer but whether these changes occur early in tumour development is unclear. Here, the authors analyse methylation events in breast cancer and adjacent normal pairs, and show that methylation changes in the normal tissue are also found in the tumour, suggesting that some of these events occur early in cancer.
doi:10.1038/ncomms10478
PMCID: PMC4740178  PMID: 26823093
8.  Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC) 
Jim, Heather S.L. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Sieh, Weiva | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Vierkant, Robert A. | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Thomsen, Lotte | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Palmieri Weber, Rachel | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Schernhammer, Eva | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Amankwah, Ernest | Berchuck, Andrew | Schildkraut, Joellen M. | Kelemen, Linda E. | Ramus, Susan J. | Monteiro, Alvaro N.A. | Goode, Ellen L. | Narod, Steven A. | Gayther, Simon A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
PMCID: PMC4722961  PMID: 26807442
9.  Epithelial-Mesenchymal Transition (EMT) gene variants and Epithelial Ovarian Cancer (EOC) risk 
Amankwah, Ernest K. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chen, Zhihua | Chen, Y. Ann | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Jim, Heather | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Kelemen, Linda E. | Berchuck, Andrew | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N.A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Genetic epidemiology  2015;39(8):689-697.
Introduction
Epithelial-mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to EOC risk have been based on small sample sizes and none have sought replication in an independent population.
Methods
We screened 1254 SNPs in 296 genes in a discovery phase using data from a genome-wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT-related genes that were nominally (p<0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive-cancer patients and 23,447 controls. A p-value <0.05 and a false discovery rate (FDR) <0.2 was considered statistically significant.
Results
In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (OR=1.16, 95%CI=1.07–1.25, p=0.0003, FDR=0.19), while F8 rs7053448 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), F8 rs7058826 (OR=1.69, 95%CI=1.27–2.24, p=0.0003, FDR=0.12), and CAPN13 rs1983383 (OR=0.79, 95%CI=0.69–0.90, p=0.0005, FDR=0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements.
Conclusion
These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.
doi:10.1002/gepi.21921
PMCID: PMC4721602  PMID: 26399219
ovarian cancer; epithelial-mesenchymal transition; single nucleotide polymorphisms
10.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
11.  Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1 
Cheng, Timothy HT | Thompson, Deborah | Painter, Jodie | O’Mara, Tracy | Gorman, Maggie | Martin, Lynn | Palles, Claire | Jones, Angela | Buchanan, Daniel D. | Ko Win, Aung | Hopper, John | Jenkins, Mark | Lindor, Noralane M. | Newcomb, Polly A. | Gallinger, Steve | Conti, David | Schumacher, Fred | Casey, Graham | Giles, Graham G | Pharoah, Paul | Peto, Julian | Cox, Angela | Swerdlow, Anthony | Couch, Fergus | Cunningham, Julie M | Goode, Ellen L | Winham, Stacey J | Lambrechts, Diether | Fasching, Peter | Burwinkel, Barbara | Brenner, Hermann | Brauch, Hiltrud | Chang-Claude, Jenny | Salvesen, Helga B. | Kristensen, Vessela | Darabi, Hatef | Li, Jingmei | Liu, Tao | Lindblom, Annika | Hall, Per | de Polanco, Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Aguiar Jnr, Samuel | Teixeira, Manuel R. | Dunning, Alison M | Dennis, Joe | Otton, Geoffrey | Proietto, Tony | Holliday, Elizabeth | Attia, John | Ashton, Katie | Scott, Rodney J | McEvoy, Mark | Dowdy, Sean C | Fridley, Brooke L | Werner, Henrica MJ | Trovik, Jone | Njolstad, Tormund S | Tham, Emma | Mints, Miriam | Runnebaum, Ingo | Hillemanns, Peter | Dörk, Thilo | Amant, Frederic | Schrauwen, Stefanie | Hein, Alexander | Beckmann, Matthias W | Ekici, Arif | Czene, Kamila | Meindl, Alfons | Bolla, Manjeet K | Michailidou, Kyriaki | Tyrer, Jonathan P | Wang, Qin | Ahmed, Shahana | Healey, Catherine S | Shah, Mitul | Annibali, Daniela | Depreeuw, Jeroen | Al-Tassan, Nada A. | Harris, Rebecca | Meyer, Brian F. | Whiffin, Nicola | Hosking, Fay J | Kinnersley, Ben | Farrington, Susan M. | Timofeeva, Maria | Tenesa, Albert | Campbell, Harry | Haile, Robert W. | Hodgson, Shirley | Carvajal-Carmona, Luis | Cheadle, Jeremy P. | Easton, Douglas | Dunlop, Malcolm | Houlston, Richard | Spurdle, Amanda | Tomlinson, Ian
Scientific Reports  2015;5:17369.
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10−9) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10−8), with the alleles showing opposite effects on the risks of the two cancers.
doi:10.1038/srep17369
PMCID: PMC4664893  PMID: 26621817
12.  Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B. | Behrens, Sabine | Goode, Ellen L. | Bolla, Manjeet K. | Dennis, Joe | Dunning, Alison M. | Easton, Douglas F. | Wang, Qin | Benitez, Javier | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Fasching, Peter A. | Haeberle, Lothar | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marmé, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Nielsen, Sune F. | Nordestgaard, Børge G. | González-Neira, Anna | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Fagerholm, Rainer | Dörk, Thilo | Bogdanova, Natalia V. | Mannermaa, Arto | Hartikainen, Jaana M. | Van Dijck, Laurien | Smeets, Ann | Flesch-Janys, Dieter | Eilber, Ursula | Radice, Paolo | Peterlongo, Paolo | Couch, Fergus J. | Hallberg, Emily | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Goldberg, Mark S. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Winqvist, Robert | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | García-Closas, Montserrat | Figueroa, Jonine | Czene, Kamila | Brand, Judith S. | Darabi, Hatef | Eriksson, Mikael | Hall, Per | Li, Jingmei | Cox, Angela | Cross, Simon S. | Pharoah, Paul D. P. | Shah, Mitul | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Ademuyiwa, Foluso | Ambrosone, Christine B. | Swerdlow, Anthony | Jones, Michael | Chang-Claude, Jenny
Human Genetics  2015;135:137-154.
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1616-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-015-1616-8
PMCID: PMC4698282  PMID: 26621531
13.  Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade 
Purrington, Kristen S. | Slettedahl, Seth | Bolla, Manjeet K. | Michailidou, Kyriaki | Czene, Kamila | Nevanlinna, Heli | Bojesen, Stig E. | Andrulis, Irene L. | Cox, Angela | Hall, Per | Carpenter, Jane | Yannoukakos, Drakoulis | Haiman, Christopher A. | Fasching, Peter A. | Mannermaa, Arto | Winqvist, Robert | Brenner, Hermann | Lindblom, Annika | Chenevix-Trench, Georgia | Benitez, Javier | Swerdlow, Anthony | Kristensen, Vessela | Guénel, Pascal | Meindl, Alfons | Darabi, Hatef | Eriksson, Mikael | Fagerholm, Rainer | Aittomäki, Kristiina | Blomqvist, Carl | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Wang, Xianshu | Olswold, Curtis | Olson, Janet E. | Mulligan, Anna Marie | Knight, Julia A. | Tchatchou, Sandrine | Reed, Malcolm W.R. | Cross, Simon S. | Liu, Jianjun | Li, Jingmei | Humphreys, Keith | Clarke, Christine | Scott, Rodney | Fostira, Florentia | Fountzilas, George | Konstantopoulou, Irene | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Ekici, Arif B. | Hartmann, Arndt | Beckmann, Matthias W. | Hartikainen, Jaana M. | Kosma, Veli-Matti | Kataja, Vesa | Jukkola-Vuorinen, Arja | Pylkäs, Katri | Kauppila, Saila | Dieffenbach, Aida Karina | Stegmaier, Christa | Arndt, Volker | Margolin, Sara | Balleine, Rosemary | Arias Perez, Jose Ignacio | Pilar Zamora, M. | Menéndez, Primitiva | Ashworth, Alan | Jones, Michael | Orr, Nick | Arveux, Patrick | Kerbrat, Pierre | Truong, Thérèse | Bugert, Peter | Toland, Amanda E. | Ambrosone, Christine B. | Labrèche, France | Goldberg, Mark S. | Dumont, Martine | Ziogas, Argyrios | Lee, Eunjung | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Ficarazzi, Filomena | Barile, Monica | Peterlongo, Paolo | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Brüning, Thomas | Ko, Yon-Dschun | Van Deurzen, Carolien H.M. | Martens, John W.M. | Kriege, Mieke | Figueroa, Jonine D. | Chanock, Stephen J. | Lissowska, Jolanta | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Schneeweiss, Andreas | Tapper, William J. | Gerty, Susan M. | Durcan, Lorraine | Mclean, Catriona | Milne, Roger L. | Baglietto, Laura | dos Santos Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Van'T Veer, Laura J. | Cornelissen, Sten | Försti, Asta | Torres, Diana | Rüdiger, Thomas | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Weltens, Caroline | Floris, Giuseppe | Moisse, Matthieu | Dennis, Joe | Wang, Qin | Dunning, Alison M. | Shah, Mitul | Brown, Judith | Simard, Jacques | Anton-Culver, Hoda | Neuhausen, Susan L. | Hopper, John L. | Bogdanova, Natalia | Dörk, Thilo | Zheng, Wei | Radice, Paolo | Jakubowska, Anna | Lubinski, Jan | Devillee, Peter | Brauch, Hiltrud | Hooning, Maartje | García-Closas, Montserrat | Sawyer, Elinor | Burwinkel, Barbara | Marmee, Frederick | Eccles, Diana M. | Giles, Graham G. | Peto, Julian | Schmidt, Marjanka | Broeks, Annegien | Hamann, Ute | Chang-Claude, Jenny | Lambrechts, Diether | Pharoah, Paul D.P. | Easton, Douglas | Pankratz, V. Shane | Slager, Susan | Vachon, Celine M. | Couch, Fergus J.
Human Molecular Genetics  2014;23(22):6034-6046.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
doi:10.1093/hmg/ddu300
PMCID: PMC4204763  PMID: 24927736
14.  SNP-SNP interaction analysis of NF-κB signaling pathway on breast cancer survival 
Oncotarget  2015;6(35):37979-37994.
In breast cancer, constitutive activation of NF-κB has been reported, however, the impact of genetic variation of the pathway on patient prognosis has been little studied. Furthermore, a combination of genetic variants, rather than single polymorphisms, may affect disease prognosis. Here, in an extensive dataset (n = 30,431) from the Breast Cancer Association Consortium, we investigated the association of 917 SNPs in 75 genes in the NF-κB pathway with breast cancer prognosis. We explored SNP-SNP interactions on survival using the likelihood-ratio test comparing multivariate Cox’ regression models of SNP pairs without and with an interaction term. We found two interacting pairs associating with prognosis: patients simultaneously homozygous for the rare alleles of rs5996080 and rs7973914 had worse survival (HRinteraction 6.98, 95% CI=3.3-14.4, P = 1.42E-07), and patients carrying at least one rare allele for rs17243893 and rs57890595 had better survival (HRinteraction 0.51, 95% CI=0.3-0.6, P = 2.19E-05). Based on in silico functional analyses and literature, we speculate that the rs5996080 and rs7973914 loci may affect the BAFFR and TNFR1/TNFR3 receptors and breast cancer survival, possibly by disturbing both the canonical and non-canonical NF-κB pathways or their dynamics, whereas, rs17243893-rs57890595 interaction on survival may be mediated through TRAF2-TRAIL-R4 interplay. These results warrant further validation and functional analyses.
PMCID: PMC4741978  PMID: 26317411
breast cancer; survival analysis; SNP-SNP interaction; NF-κB pathway
15.  Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer 
Lawrenson, Kate | Li, Qiyuan | Kar, Siddhartha | Seo, Ji-Heui | Tyrer, Jonathan | Spindler, Tassja J. | Lee, Janet | Chen, Yibu | Karst, Alison | Drapkin, Ronny | Aben, Katja K. H. | Anton-Culver, Hoda | Antonenkova, Natalia | Baker, Helen | Bandera, Elisa V. | Bean, Yukie | Beckmann, Matthias W. | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bruinsma, Fiona | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Chenevix-Trench, Georgia | Chen, Anne | Chen, Zhihua | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | Dennis, Joe | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | du Bois, Andreas | Dürst, Matthias | Eccles, Diana | Easton, Douglas T. | Edwards, Robert P. | Eilber, Ursula | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goode, Ellen L. | Goodman, Marc T. | Grownwald, Jacek | Harrington, Patricia | Harter, Philipp | Hasmad, Hanis Nazihah | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A. T. | Hillemanns, Peter | Hogdall, Estrid | Hogdall, Claus | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | James, Paul | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kruger Kjaer, Susanne | Kelemen, Linda E. | Kellar, Melissa | Kelley, Joseph L. | Kiemeney, Lambertus A. | Krakstad, Camilla | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F. A. G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | Nevanlinna, Heli | McNeish, Ian | Menon, Usha | Modugno, Francesmary | Moysich, Kirsten B. | Narod, Steven A. | Nedergaard, Lotte | Ness, Roberta B. | Azmi, Mat Adenan Noor | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Permuth-Wey, Jennifer | Phelan, Catherine M. | Pike, Malcolm C. | Poole, Elizabeth M. | Ramus, Susan J. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schildkraut, Joellen M. | Schwaab, Ira | Sellers, Thomas A. | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Sucheston, Lara | Tangen, Ingvild L. | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Timorek, Agnieszka | Tsai, Ya-Yu | Tworoger, Shelley S. | van Altena, Anne M. | Van Nieuwenhuysen, Els | Vergote, Ignace | Vierkant, Robert A. | Wang-Gohrke, Shan | Walsh, Christine | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Woo, Yin-Ling | Wu, Xifeng | Wu, Anna H. | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Monteiro, Alvaro | Pharoah, Paul D. | Gayther, Simon A. | Freedman, Matthew L.
Nature Communications  2015;6:8234.
Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10−5). For three cis-eQTL associations (P<1.4 × 10−3, FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10−10 for risk variants (P<10−4) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Genome-wide association studies have identified regions which confer risk of high-grade serous epithelial ovarian cancer. Here the authors use expression quantitative train locus analysis to identify candidate genes and functionally characterise them, identifying a role for HOXD9 in ovarian cancer.
doi:10.1038/ncomms9234
PMCID: PMC4580986  PMID: 26391404
16.  Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk 
Kelemen, Linda E. | Terry, Kathryn L. | Goodman, Marc T. | Webb, Penelope M. | Bandera, Elisa V. | McGuire, Valerie | Rossing, Mary Anne | Wang, Qinggang | Dicks, Ed | Tyrer, Jonathan P. | Song, Honglin | Kupryjanczyk, Jolanta | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Timorek, Agnieszka | Menon, Usha | Gentry-Maharaj, Aleksandra | Gayther, Simon A. | Ramus, Susan J. | Narod, Steven A. | Risch, Harvey A. | McLaughlin, John R. | Siddiqui, Nadeem | Glasspool, Rosalind | Paul, James | Carty, Karen | Gronwald, Jacek | Lubiński, Jan | Jakubowska, Anna | Cybulski, Cezary | Kiemeney, Lambertus A. | Massuger, Leon F. A. G. | van Altena, Anne M. | Aben, Katja K. H. | Olson, Sara H. | Orlow, Irene | Cramer, Daniel W. | Levine, Douglas A. | Bisogna, Maria | Giles, Graham G. | Southey, Melissa C. | Bruinsma, Fiona | Kjær, Susanne Krüger | Høgdall, Estrid | Jensen, Allan | Høgdall, Claus K. | Lundvall, Lene | Engelholm, Svend-Aage | Heitz, Florian | du Bois, Andreas | Harter, Philipp | Schwaab, Ira | Butzow, Ralf | Nevanlinna, Heli | Pelttari, Liisa M. | Leminen, Arto | Thompson, Pamela J. | Lurie, Galina | Wilkens, Lynne R. | Lambrechts, Diether | Van Nieuwenhuysen, Els | Lambrechts, Sandrina | Vergote, Ignace | Beesley, Jonathan | Fasching, Peter A. | Beckmann, Matthias W. | Hein, Alexander | Ekici, Arif B. | Doherty, Jennifer A. | Wu, Anna H. | Pearce, Celeste L. | Pike, Malcolm C. | Stram, Daniel | Chang-Claude, Jenny | Rudolph, Anja | Dörk, Thilo | Dürst, Matthias | Hillemanns, Peter | Runnebaum, Ingo B. | Bogdanova, Natalia | Antonenkova, Natalia | Odunsi, Kunle | Edwards, Robert P. | Kelley, Joseph L. | Modugno, Francesmary | Ness, Roberta B. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Fridley, Brooke L. | Vierkant, Robert A. | Cunningham, Julie M. | Wu, Xifeng | Lu, Karen | Liang, Dong | Hildebrandt, Michelle A.T. | Weber, Rachel Palmieri | Iversen, Edwin S. | Tworoger, Shelley S. | Poole, Elizabeth M. | Salvesen, Helga B. | Krakstad, Camilla | Bjorge, Line | Tangen, Ingvild L. | Pejovic, Tanja | Bean, Yukie | Kellar, Melissa | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Garcia-Closas, Montserrat | Campbell, Ian G. | Eccles, Diana | Whittemore, Alice S. | Sieh, Weiva | Rothstein, Joseph H. | Anton-Culver, Hoda | Ziogas, Argyrios | Phelan, Catherine M. | Moysich, Kirsten B. | Goode, Ellen L. | Schildkraut, Joellen M. | Berchuck, Andrew | Pharoah, Paul D.P. | Sellers, Thomas A. | Brooks-Wilson, Angela | Cook, Linda S. | Le, Nhu D.
Molecular nutrition & food research  2014;58(10):2023-2035.
Scope
We re-evaluated previously reported associations between variants in pathways of one-carbon (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.
Methods and Results
Odds ratios (OR) for 446 genetic variants were estimated among 13,410 OC cases and 22,635 controls and among 2,281 cases and 3,444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for DPYD variants rs11587873 (OR=0.92, P=6x10−5) and rs828054 (OR=1.06, P=1x10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT and TYMS, also interacted significantly with folate in a multi-variant analysis (corrected P=9.9x10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in one-carbon transfer, previously reported with OC, suggested lower risk at higher folate (Pinteraction=0.03-0.006).
Conclusions
Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-byfolate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
doi:10.1002/mnfr.201400068
PMCID: PMC4197821  PMID: 25066213
case-control; DPYD; folate; polymorphism; SHMT1
17.  Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer 
Michailidou, Kyriaki | Beesley, Jonathan | Lindstrom, Sara | Canisius, Sander | Dennis, Joe | Lush, Michael | Maranian, Mel J | Bolla, Manjeet K | Wang, Qin | Shah, Mitul | Perkins, Barbara J | Czene, Kamila | Eriksson, Mikael | Darabi, Hatef | Brand, Judith S | Bojesen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | Nielsen, Sune F | Rahman, Nazneen | Turnbull, Clare | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | dos-Santos-Silva, Isabel | Chang-Claude, Jenny | Flesch-Janys, Dieter | Rudolph, Anja | Eilber, Ursula | Behrens, Sabine | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Aaltonen, Kirsimari | Ahsan, Habibul | Kibriya, Muhammad G | Whittemore, Alice S | John, Esther M | Malone, Kathleen E | Gammon, Marilie D | Santella, Regina M | Ursin, Giske | Makalic, Enes | Schmidt, Daniel F | Casey, Graham | Hunter, David J | Gapstur, Susan M | Gaudet, Mia M | Diver, W Ryan | Haiman, Christopher A | Schumacher, Fredrick | Henderson, Brian E | Le Marchand, Loic | Berg, Christine D | Chanock, Stephen | Figueroa, Jonine | Hoover, Robert N | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | van Limbergen, Erik | Schmidt, Marjanka K | Broeks, Annegien | Verhoef, Senno | Cornelissen, Sten | Couch, Fergus J | Olson, Janet E | Hallberg, Emily | Vachon, Celine | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A | van der Luijt, Rob B | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K | Yoo, Keun-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Guénel, Pascal | Truong, Thérèse | Mulot, Claire | Sanchez, Marie | Burwinkel, Barbara | Marme, Frederik | Surowy, Harald | Sohn, Christof | Wu, Anna H | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O | González-Neira, Anna | Benitez, Javier | Zamora, M Pilar | Perez, Jose Ignacio Arias | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cox, Angela | Cross, Simon S | Reed, Malcolm WR | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Lindblom, Annika | Margolin, Sara | Teo, Soo Hwang | Yip, Cheng Har | Taib, Nur Aishah Mohd | TAN, Gie-Hooi | Hooning, Maartje J | Hollestelle, Antoinette | Martens, John WM | Collée, J Margriet | Blot, William | Signorello, Lisa B | Cai, Qiuyin | Hopper, John L | Southey, Melissa C | Tsimiklis, Helen | Apicella, Carmel | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Hou, Ming-Feng | Kristensen, Vessela N | Nord, Silje | Alnaes, Grethe I Grenaker | Giles, Graham G | Milne, Roger L | McLean, Catriona | Canzian, Federico | Trichopoulos, Dmitrios | Peeters, Petra | Lund, Eiliv | Sund, Malin | Khaw, Kay-Tee | Gunter, Marc J | Palli, Domenico | Mortensen, Lotte Maxild | Dossus, Laure | Huerta, Jose-Maria | Meindl, Alfons | Schmutzler, Rita K | Sutter, Christian | Yang, Rongxi | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Chan, Ching Wan | Fasching, Peter A | Hein, Alexander | Beckmann, Matthias W | Haeberle, Lothar | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk J | Swerdlow, Anthony J | Brinton, Louise | Garcia-Closas, Montserrat | Zheng, Wei | Halverson, Sandra L | Shrubsole, Martha | Long, Jirong | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Bogdanova, Natalia V | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Devilee, Peter | Tollenaar, Robert AEM | Seynaeve, Caroline | Van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Huzarski, Tomasz | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Kabisch, Maria | Torres, Diana | Neuhausen, Susan L | Anton-Culver, Hoda | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Healey, Catherine S | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Simard, Jacques | Pharoah, Paul PDP | Kraft, Peter | Dunning, Alison M | Chenevix-Trench, Georgia | Hall, Per | Easton, Douglas F
Nature genetics  2015;47(4):373-380.
Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1.
doi:10.1038/ng.3242
PMCID: PMC4549775  PMID: 25751625
18.  The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial 
Introduction
Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear.
Methods
This retrospective analysis was performed using data from the SUCCESS A trial, in which 3754 patients with high-risk early breast cancer were randomized to anthracycline- and taxane-based chemotherapy with or without gemcitabine. Patients were classified as underweight/normal weight (body mass index (BMI) < 25.0), overweight (BMI 25.0–29.9), slightly obese (BMI 30.0–34.9), moderately obese (BMI 35.0–39.9) and severely obese (BMI ≥ 40.0), and the effect of BMI on disease-free survival (DFS) and overall survival (OS) was evaluated (median follow-up 65 months). In addition, subgroup analyses were conducted to assess the effect of BMI in luminal A-like, luminal B-like, HER2 (human epidermal growth factor 2)-positive and triple-negative tumors.
Results
Multivariate analyses revealed an independent prognostic effect of BMI on DFS (p = 0.001) and OS (p = 0.005). Compared with underweight/normal weight patients, severely obese patients had worse DFS (hazard ratio (HR) 2.70, 95 % confidence interval (CI) 1.71–4.28, p < 0.001) and OS (HR 2.79, 95 % CI 1.63–4.77, p < 0.001), while moderately obese, slightly obese and overweight patients did not differ from underweight/normal weight patients with regard to DFS or OS. Subgroup analyses showed a similar significant effect of BMI on DFS and OS in patients with triple-negative breast cancer (TNBC), but not in patients with other tumor subtypes.
Conclusions
Severe obesity (BMI ≥ 40) significantly worsens prognosis in early breast cancer patients, particularly for triple-negative tumors.
Trial registration
Clinicaltrials.gov NCT02181101. Registered September 2005.
doi:10.1186/s13058-015-0639-3
PMCID: PMC4575482  PMID: 26385214
19.  A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density 
Introduction
Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.
Methods
The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (Pint) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.
Results
No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted Pint <0.0004) was observed with rs9358531 6.5kb 5′ of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted Pint <0.002), but solely among cases (unadjusted Pint SNP×MHT×case-status <0.02).
Conclusions
The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-015-0625-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-015-0625-9
PMCID: PMC4537547  PMID: 26275715
20.  Identification of six new susceptibility loci for invasive epithelial ovarian cancer 
Kuchenbaecker, Karoline B. | Ramus, Susan J. | Tyrer, Jonathan | Lee, Andrew | Shen, Howard C. | Beesley, Jonathan | Lawrenson, Kate | McGuffog, Lesley | Healey, Sue | Lee, Janet M. | Spindler, Tassja J. | Lin, Yvonne G. | Pejovic, Tanja | Bean, Yukie | Li, Qiyuan | Coetzee, Simon | Hazelett, Dennis | Miron, Alexander | Southey, Melissa | Terry, Mary Beth | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas V. O. | Jønson, Lars | Gerdes, Anne-Marie | Ejlertsen, Bent | Barrowdale, Daniel | Dennis, Joe | Benitez, Javier | Osorio, Ana | Garcia, Maria Jose | Komenaka, Ian | Weitzel, Jeffrey N. | Ganschow, Pamela | Peterlongo, Paolo | Bernard, Loris | Viel, Alessandra | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Radice, Paolo | Papi, Laura | Ottini, Laura | Fostira, Florentia | Konstantopoulou, Irene | Garber, Judy | Frost, Debra | Perkins, Jo | Platte, Radka | Ellis, Steve | Godwin, Andrew K. | Schmutzler, Rita Katharina | Meindl, Alfons | Engel, Christoph | Sutter, Christian | Sinilnikova, Olga M. | Damiola, Francesca | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Claes, Kathleen | De Leeneer, Kim | Kirk, Judy | Rodriguez, Gustavo C. | Piedmonte, Marion | O'Malley, David M. | de la Hoya, Miguel | Caldes, Trinidad | Aittomäki, Kristiina | Nevanlinna, Heli | Collée, J. Margriet | Rookus, Matti A. | Oosterwijk, Jan C. | Tihomirova, Laima | Tung, Nadine | Hamann, Ute | Isaacs, Claudine | Tischkowitz, Marc | Imyanitov, Evgeny N. | Caligo, Maria A. | Campbell, Ian | Hogervorst, Frans B.L. | Olah, Edith | Diez, Orland | Blanco, Ignacio | Brunet, Joan | Lazaro, Conxi | Pujana, Miquel Angel | Jakubowska, Anna | Gronwald, Jacek | Lubinski, Jan | Sukiennicki, Grzegorz | Barkardottir, Rosa B. | Plante, Marie | Simard, Jacques | Soucy, Penny | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Pankratz, Vernon S. | Wang, Xianshu | Lindor, Noralane | Szabo, Csilla I. | Kauff, Noah | Vijai, Joseph | Aghajanian, Carol A. | Pfeiler, Georg | Berger, Andreas | Singer, Christian F. | Tea, Muy-Kheng | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Tchatchou, Sandrine | Andrulis, Irene L. | Glendon, Gord | Toland, Amanda Ewart | Jensen, Uffe Birk | Kruse, Torben A. | Thomassen, Mads | Bojesen, Anders | Zidan, Jamal | Friedman, Eitan | Laitman, Yael | Soller, Maria | Liljegren, Annelie | Arver, Brita | Einbeigi, Zakaria | Stenmark-Askmalm, Marie | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Rebbeck, Timothy R. | Nathanson, Katherine L. | Domchek, Susan M. | Lu, Karen H. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Nieuwenhuysen, Els Van | Vergote, Ignace | Lambrechts, Sandrina | Dicks, Ed | Doherty, Jennifer A. | Wicklund, Kristine G. | Rossing, Mary Anne | Rudolph, Anja | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lele, Shashi | Wilkens, Lynne R. | Goodman, Marc T. | Thompson, Pamela J. | Shvetsov, Yurii B. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Pelttari, Liisa M. | Butzow, Ralf | Modugno, Francesmary | Kelley, Joseph L. | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Matsuo, Keitaro | Hosono, Satoyo | Orsulic, Sandra | Jensen, Allan | Kjaer, Susanne Kruger | Hogdall, Estrid | Hasmad, Hanis Nazihah | Noor Azmi, Mat Adenan | Teo, Soo-Hwang | Woo, Yin-Ling | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Bruinsma, Fiona | Giles, Graham G. | Liang, Dong | Hildebrandt, Michelle A.T. | Wu, Xifeng | Levine, Douglas A. | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Concannon, Patrick | Weber, Rachel Palmieri | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Orlow, Irene | Olson, Sara H. | Krakstad, Camilla | Salvesen, Helga B. | Tangen, Ingvild L. | Bjorge, Line | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Kellar, Melissa | Brooks-Wilson, Angela | Kelemen, Linda E. | Cook, Linda S. | Le, Nhu D. | Cybulski, Cezary | Yang, Hannah | Lissowska, Jolanta | Brinton, Louise A. | Wentzensen, Nicolas | Hogdall, Claus | Lundvall, Lene | Nedergaard, Lotte | Baker, Helen | Song, Honglin | Eccles, Diana | McNeish, Ian | Paul, James | Carty, Karen | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S. | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Ji, Bu-Tian | Zheng, Wei | Shu, Xiao-Ou | Gao, Yu-Tang | Rosen, Barry | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Monteiro, Alvaro N. | Chen, Ann | Lin, Hui-Yi | Permuth-Wey, Jenny | Sellers, Thomas A. | Tsai, Ya-Yu | Chen, Zhihua | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Harrington, Patricia | Lee, Alice W. | Wu, Anna H. | Pearce, Celeste L. | Coetzee, Gerhard A. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Timorek, Agnieszka | Rzepecka, Iwona K. | Kupryjanczyk, Jolanta | Freedman, Matt | Noushmehr, Houtan | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Gayther, Simon | Pharoah, Paul P. | Antoniou, Antonis C. | Chenevix-Trench, Georgia
Nature genetics  2015;47(2):164-171.
doi:10.1038/ng.3185
PMCID: PMC4445140  PMID: 25581431
21.  ABCA Transporter Gene Expression and Poor Outcome in Epithelial Ovarian Cancer 
Background
ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.
Methods
The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA–mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan–Meier analysis and log-rank tests. All statistical tests were two-sided.
Results
Associations with outcome were observed with ABC transporters of the “A” subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e−6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.
Conclusions
Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
doi:10.1093/jnci/dju149
PMCID: PMC4110473  PMID: 24957074
22.  Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk 
Chornokur, Ganna | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Amankwah, Ernest K. | Qu, Xiaotao | Tsai, Ya-Yu | Jim, Heather S. L. | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Dicks, Ed | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harrington, Patricia | Harter, Philipp | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A. T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kelemen, Linda E. | Kellar, Mellissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F. A. G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Iain | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Weber, Rachel Palmieri | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schernhammer, Eva | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Sieh, Weiva | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Thomsen, Lotte | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vierkant, Robert A. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Hasmad, Hanis N. | Berchuck, Andrew | Iversen, Edwin S. | Schildkraut, Joellen M. | Ramus, Susan J. | Goode, Ellen L. | Monteiro, Alvaro N. A. | Gayther, Simon A. | Narod, Steven A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
PLoS ONE  2015;10(6):e0128106.
Background
Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.
Methods
In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.
Results
The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).
Conclusion
These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.
doi:10.1371/journal.pone.0128106
PMCID: PMC4474865  PMID: 26091520
23.  Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer 
Purrington, Kristen S. | Slager, Susan | Eccles, Diana | Yannoukakos, Drakoulis | Fasching, Peter A. | Miron, Penelope | Carpenter, Jane | Chang-Claude, Jenny | Martin, Nicholas G. | Montgomery, Grant W. | Kristensen, Vessela | Anton-Culver, Hoda | Goodfellow, Paul | Tapper, William J. | Rafiq, Sajjad | Gerty, Susan M. | Durcan, Lorraine | Konstantopoulou, Irene | Fostira, Florentia | Vratimos, Athanassios | Apostolou, Paraskevi | Konstanta, Irene | Kotoula, Vassiliki | Lakis, Sotiris | Dimopoulos, Meletios A. | Skarlos, Dimosthenis | Pectasides, Dimitrios | Fountzilas, George | Beckmann, Matthias W. | Hein, Alexander | Ruebner, Matthias | Ekici, Arif B. | Hartmann, Arndt | Schulz-Wendtland, Ruediger | Renner, Stefan P. | Janni, Wolfgang | Rack, Brigitte | Scholz, Christoph | Neugebauer, Julia | Andergassen, Ulrich | Lux, Michael P. | Haeberle, Lothar | Clarke, Christine | Pathmanathan, Nirmala | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Olson, Janet E. | Ingle, James N. | Olswold, Curtis | Slettedahl, Seth | Eckel-Passow, Jeanette E. | Anderson, S.Keith | Visscher, Daniel W. | Cafourek, Victoria L. | Sicotte, Hugues | Prodduturi, Naresh | Weiderpass, Elisabete | Bernstein, Leslie | Ziogas, Argyrios | Ivanovich, Jennifer | Giles, Graham G. | Baglietto, Laura | Southey, Melissa | Kosma, Veli-Matti | Fischer, Hans-Peter | Reed, Malcom W.R. | Cross, Simon S. | Deming-Halverson, Sandra | Shrubsole, Martha | Cai, Qiuyin | Shu, Xiao-Ou | Daly, Mary | Weaver, JoEllen | Ross, Eric | Klemp, Jennifer | Sharma, Priyanka | Torres, Diana | Rüdiger, Thomas | Wölfing, Heidrun | Ulmer, Hans-Ulrich | Försti, Asta | Khoury, Thaer | Kumar, Shicha | Pilarski, Robert | Shapiro, Charles L. | Greco, Dario | Heikkilä, Päivi | Aittomäki, Kristiina | Blomqvist, Carl | Irwanto, Astrid | Liu, Jianjun | Pankratz, Vernon Shane | Wang, Xianshu | Severi, Gianluca | Mannermaa, Arto | Easton, Douglas | Hall, Per | Brauch, Hiltrud | Cox, Angela | Zheng, Wei | Godwin, Andrew K. | Hamann, Ute | Ambrosone, Christine | Toland, Amanda Ewart | Nevanlinna, Heli | Vachon, Celine M. | Couch, Fergus J.
Carcinogenesis  2013;35(5):1012-1019.
Summary
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10− 8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10− 4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10− 9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10− 69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
doi:10.1093/carcin/bgt404
PMCID: PMC4004200  PMID: 24325915
24.  Genome-wide Association Study of Subtype-Specific Epithelial Ovarian Cancer Risk Alleles Using Pooled DNA 
Earp, Madalene A. | Kelemen, Linda E. | Magliocco, Anthony M. | Swenerton, Kenneth D. | Chenevix–Trench, Georgia | Lu, Yi | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fasching, Peter A. | Lambrechts, Diether | Despierre, Evelyn | Vergote, Ignace | Lambrechts, Sandrina | Doherty, Jennifer A. | Rossing, Mary Anne | Chang-Claude, Jenny | Rudolph, Anja | Friel, Grace | Moysich, Kirsten B. | Odunsi, Kunle | Sucheston-Campbell, Lara | Lurie, Galina | Goodman, Marc T. | Carney, Michael E. | Thompson, Pamela J. | Runnebaum, Ingo B. | Dürst, Matthias | Hillemanns, Peter | Dörk, Thilo | Antonenkova, Natalia | Bogdanova, Natalia | Leminen, Arto | Nevanlinna, Heli | Pelttari, Liisa M. | Butzow, Ralf | Bunker, Clareann H. | Modugno, Francesmary | Edwards, Robert P. | Ness, Roberta B. | du Bois, Andreas | Heitz, Florian | Schwaab, Ira | Harter, Philipp | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjær, Susanne K. | Høgdall, Claus K. | Høgdall, Estrid | Lundvall, Lene | Sellers, Thomas A. | Fridley, Brooke L. | Goode, Ellen L. | Cunningham, Julie M. | Vierkant, Robert A. | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | Southey, Melissa C. | Liang, Dong | Wu, Xifeng | Lu, Karen | Hildebrandt, Michelle A.T. | Levine, Douglas A. | Bisogna, Maria | Schildkraut, Joellen M. | Iversen, Edwin S. | Weber, Rachel Palmieri | Berchuck, Andrew | Cramer, Daniel W. | Terry, Kathryn L. | Poole, Elizabeth M. | Tworoger, Shelley S. | Bandera, Elisa V. | Chandran, Urmila | Orlow, Irene | Olson, Sara H. | Wik, Elisabeth | Salvesen, Helga B. | Bjorge, Line | Halle, Mari K. | van Altena, Anne M. | Aben, Katja K.H. | Kiemeney, Lambertus A. | Massuger, Leon F.A.G. | Pejovic, Tanja | Bean, Yukie T. | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Wentzensen, Nicolas | Brinton, Louise A. | Lissowska, Jolanta | Garcia–Closas, Montserrat | Dicks, Ed | Dennis, Joe | Easton, Douglas F. | Song, Honglin | Tyrer, Jonathan P. | Pharoah, Paul D. P. | Eccles, Diana | Campbell, Ian G. | Whittemore, Alice S. | McGuire, Valerie | Sieh, Weiva | Rothstein, Joseph H. | Flanagan, James M. | Paul, James | Brown, Robert | Phelan, Catherine M. | Risch, Harvey A. | McLaughlin, John R. | Narod, Steven A. | Ziogas, Argyrios | Anton-Culver, Hoda | Gentry-Maharaj, Aleksandra | Menon, Usha | Gayther, Simon A. | Ramus, Susan J. | Wu, Anna H. | Pearce, Celeste L. | Pike, Malcolm C. | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K | Szafron, Lukasz M | Kupryjanczyk, Jolanta | Cook, Linda S. | Le, Nhu D. | Brooks–Wilson, Angela
Human genetics  2013;133(5):481-497.
Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS (56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low malignant potential (LMP) serous, and 24 for invasive serous EOC), selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95% confidence intervals are reported. Nine variants tagging 6 loci were associated with subtype-specific EOC risk at P<0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR=1.17, P=0.029, n=1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P=0.014, n=2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR=0.86, P=0.0043, n=892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR=0.84, P=0.0007) and LMP serous EOC risk remained statistically significant at P<0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
doi:10.1007/s00439-013-1383-3
PMCID: PMC4063682  PMID: 24190013
histological subtype; serous; endometrioid; clear cell; mucinous; BPIL2
25.  Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk 
Nature communications  2014;5:5303.
Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci.
doi:10.1038/ncomms6303
PMCID: PMC4320806  PMID: 25342443

Results 1-25 (127)