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1.  Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer 
Purpose
To analyse the effect of germline mutations in BRCA1 and BRCA2 on mortality in ovarian cancer patients up to ten years after diagnosis.
Experimental Design
We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival-time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analysed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analysed using Fine and Gray model.
Results
The combined 10-year overall survival was 30% (95% CI, 28%-31%) for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The hazard ratio for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at ·4.8 years. For BRCA2, the hazard ratio was 0.42 at time zero and increased over time (predicted to become greater than one at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors, and to ovarian cancer specific mortality.
Conclusions
BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and, in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.
doi:10.1158/1078-0432.CCR-14-2497
PMCID: PMC4338615  PMID: 25398451
Ovarian cancer; Epithelial ovarian cancer; BRCA1 gene; BRCA2 gene; Survival
2.  Annexin A1 expression in a pooled breast cancer series: association with tumor subtypes and prognosis 
BMC Medicine  2015;13:156.
Background
Annexin A1 (ANXA1) is a protein related with the carcinogenesis process and metastasis formation in many tumors. However, little is known about the prognostic value of ANXA1 in breast cancer. The purpose of this study is to evaluate the association between ANXA1 expression, BRCA1/2 germline carriership, specific tumor subtypes and survival in breast cancer patients.
Methods
Clinical-pathological information and follow-up data were collected from nine breast cancer studies from the Breast Cancer Association Consortium (BCAC) (n = 5,752) and from one study of familial breast cancer patients with BRCA1/2 mutations (n = 107). ANXA1 expression was scored based on the percentage of immunohistochemical staining in tumor cells. Survival analyses were performed using a multivariable Cox model.
Results
The frequency of ANXA1 positive tumors was higher in familial breast cancer patients with BRCA1/2 mutations than in BCAC patients, with 48.6 % versus 12.4 %, respectively; P <0.0001. ANXA1 was also highly expressed in BCAC tumors that were poorly differentiated, triple negative, EGFR-CK5/6 positive or had developed in patients at a young age. In the first 5 years of follow-up, patients with ANXA1 positive tumors had a worse breast cancer-specific survival (BCSS) than ANXA1 negative (HRadj = 1.35; 95 % CI = 1.05–1.73), but the association weakened after 10 years (HRadj = 1.13; 95 % CI = 0.91–1.40). ANXA1 was a significant independent predictor of survival in HER2+ patients (10-years BCSS: HRadj = 1.70; 95 % CI = 1.17–2.45).
Conclusions
ANXA1 is overexpressed in familial breast cancer patients with BRCA1/2 mutations and correlated with poor prognosis features: triple negative and poorly differentiated tumors. ANXA1 might be a biomarker candidate for breast cancer survival prediction in high risk groups such as HER2+ cases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0392-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0392-6
PMCID: PMC4489114  PMID: 26137966
Breast cancer; Annexin A1; BRCA1 and BRCA2 mutations
3.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005–1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers; Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
4.  Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers 
Peterlongo, Paolo | Chang-Claude, Jenny | Moysich, Kirsten B. | Rudolph, Anja | Schmutzler, Rita K. | Simard, Jacques | Soucy, Penny | Eeles, Rosalind A. | Easton, Douglas F. | Hamann, Ute | Wilkening, Stefan | Chen, Bowang | Rookus, Matti A. | Schmidt, Marjanka K | van der Baan, Frederieke H. | Spurdle, Amanda B. | Walker, Logan C. | Lose, Felicity | Maia, Ana-Teresa | Montagna, Marco | Matricardi, Laura | Lubinski, Jan | Jakubowska, Anna | Gómez Garcia, Encarna B. | Olopade, Olufunmilayo I. | Nussbaum, Robert L. | Nathanson, Katherine L. | Domchek, Susan M. | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Orsulic, Sandra | Lester, Jenny | Chung, Wendy K. | Miron, Alex | Southey, Melissa C. | Goldgar, David E. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Ding, Yuan Chun | Neuhausen, Susan L. | Hansen, Thomas V. O. | Gerdes, Anne-Marie | Ejlertsen, Bent | Jønson, Lars | Osorio, Ana | Martínez-Bouzas, Cristina | Benitez, Javier | Conway, Edye E. | Blazer, Kathleen R. | Weitzel, Jeffrey N. | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Barile, Monica | Ficarazzi, Filomena | Mariette, Frederique | Fortuzzi, Stefano | Viel, Alessandra | Giannini, Giuseppe | Papi, Laura | Martayan, Aline | Tibiletti, Maria Grazia | Radice, Paolo | Vratimos, Athanassios | Fostira, Florentia | Garber, Judy E. | Donaldson, Alan | Brewer, Carole | Foo, Claire | Evans, D. Gareth R. | Frost, Debra | Eccles, Diana | Brady, Angela | Cook, Jackie | Tischkowitz, Marc | Adlard, Julian | Barwell, Julian | Walker, Lisa | Izatt, Louise | Side, Lucy E. | Kennedy, M. John | Rogers, Mark T. | Porteous, Mary E. | Morrison, Patrick J. | Platte, Radka | Davidson, Rosemarie | Hodgson, Shirley V. | Ellis, Steve | Cole, Trevor | Godwin, Andrew K. | Claes, Kathleen | Van Maerken, Tom | Meindl, Alfons | Gehrig, Andrea | Sutter, Christian | Engel, Christoph | Niederacher, Dieter | Steinemann, Doris | Plendl, Hansjoerg | Kast, Karin | Rhiem, Kerstin | Ditsch, Nina | Arnold, Norbert | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Wang-Gohrke, Shan | Bressac-de Paillerets, Brigitte | Buecher, Bruno | Delnatte, Capucine | Houdayer, Claude | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Coupier, Isabelle | Barjhoux, Laure | Venat-Bouvet, Laurence | Golmard, Lisa | Boutry-Kryza, Nadia | Sinilnikova, Olga M. | Caron, Olivier | Pujol, Pascal | Mazoyer, Sylvie | Belotti, Muriel | Piedmonte, Marion | Friedlander, Michael L. | Rodriguez, Gustavo C. | Copeland, Larry J | de la Hoya, Miguel | Segura, Pedro Perez | Nevanlinna, Heli | Aittomäki, Kristiina | van Os, Theo A.M. | Meijers-Heijboer, Hanne E.J. | van der Hout, Annemarie H. | Vreeswijk, Maaike P.G. | Hoogerbrugge, Nicoline | Ausems, Margreet G.E.M. | van Doorn, Helena C. | Collée, J. Margriet | Olah, Edith | Diez, Orland | Blanco, Ignacio | Lazaro, Conxi | Brunet, Joan | Feliubadalo, Lidia | Cybulski, Cezary | Gronwald, Jacek | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Sukiennicki, Grzegorz | Arason, Adalgeir | Chiquette, Jocelyne | Teixeira, Manuel R. | Olswold, Curtis | Couch, Fergus J. | Lindor, Noralane M. | Wang, Xianshu | Szabo, Csilla I. | Offit, Kenneth | Corines, Marina | Jacobs, Lauren | Robson, Mark E. | Zhang, Liying | Joseph, Vijai | Berger, Andreas | Singer, Christian F. | Rappaport, Christine | Kaulich, Daphne Geschwantler | Pfeiler, Georg | Tea, Muy-Kheng M. | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Mulligan, Anna Marie | Glendon, Gord | Tchatchou, Sandrine | Andrulis, Irene L. | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Thomassen, Mads | Jensen, Uffe Birk | Laitman, Yael | Rantala, Johanna | von Wachenfeldt, Anna | Ehrencrona, Hans | Askmalm, Marie Stenmark | Borg, Åke | Kuchenbaecker, Karoline B. | McGuffog, Lesley | Barrowdale, Daniel | Healey, Sue | Lee, Andrew | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Friedman, Eitan
Background
BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and non-genetic modifying factors. In this study we evaluated the putative role of variants in many candidate modifier genes.
Methods
Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n=3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.
Results
The observed p-values of association ranged between 0.005-1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.
Conclusion
There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Impact
Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.
doi:10.1158/1055-9965.EPI-14-0532
PMCID: PMC4294951  PMID: 25336561
BRCA1 BRCA2 mutations; BRCA-mutation carriers, Breast cancer risk; Ovarian cancer risk; Candidate genetic risk modifiers
5.  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
6.  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
7.  The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients 
Oncotarget  2015;6(10):7390-7407.
We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1-mediated regulatory pathway.
PMCID: PMC4480688  PMID: 25823661
breast cancer; survival; SNP; chemotherapy; cell cycle
8.  A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium 
Milne, Roger L. | Herranz, Jesús | Michailidou, Kyriaki | Dennis, Joe | Tyrer, Jonathan P. | Zamora, M. Pilar | Arias-Perez, José Ignacio | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Wang, Qin | Bolla, Manjeet K. | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Li, Jingmei | Anton-Culver, Hoda | Neuhausen, Susan L. | Ziogas, Argyrios | Clarke, Christina A. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Chenevix-Trench, Georgia | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Dunning, Alison M. | Shah, Mitul | Guénel, Pascal | Truong, Thérèse | Sanchez, Marie | Mulot, Claire | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Collée, J. Margriet | Jager, Agnes | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Dumont, Martine | Soucy, Penny | Dörk, Thilo | Bogdanova, Natalia V. | Hamann, Ute | Försti, Asta | Rüdiger, Thomas | Ulmer, Hans-Ulrich | Fasching, Peter A. | Häberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Mariani, Paolo | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Schmidt, Marjanka K. | Broeks, Annegien | Verhoef, Senno | Rutgers, Emiel J. | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Pharoah, Paul D.P. | Hall, Per | Benítez, Javier | Malats, Núria | Easton, Douglas F.
Human Molecular Genetics  2013;23(7):1934-1946.
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
doi:10.1093/hmg/ddt581
PMCID: PMC3943524  PMID: 24242184
9.  Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions 
At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the “missing heritability.”
doi:10.1002/ijc.29099
PMCID: PMC4328144  PMID: 25077817
melanoma; fine mapping; penalized regression; heritability; genome-wide signal
10.  Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2 
Orr, Nick | Dudbridge, Frank | Dryden, Nicola | Maguire, Sarah | Novo, Daniela | Perrakis, Eleni | Johnson, Nichola | Ghoussaini, Maya | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Hogervorst, Frans B. | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Gibson, Lorna | Aitken, Zoe | Warren, Helen | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Chistof | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Sanchez, Marie | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Maria Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Hamann, Ute | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Ko, Yon-Dschun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Bogdanova, Natalia | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Beesley, Jonathan | Lambrechts, Diether | Moisse, Matthieu | Floris, Guiseppe | Beuselinck, Benoit | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Peissel, Bernard | Pensotti, Valeria | Couch, Fergus J. | Olson, Janet E. | Slettedahl, Seth | Vachon, Celine | 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 | Kristensen, Vessela | Alnæs, Grethe Grenaker | Nord, Silje | Borresen-Dale, Anne-Lise | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robertus A. E. M. | Seynaeve, Caroline M. | Van Asperen, Christi J. | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Klevebring, Daniel | Hooning, Maartje J. | Hollestelle, Antoinette | van Deurzen, Carolien H. M. | Kriege, Mieke | Hall, Per | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Perkins, Barbara J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk J. | Meindl, Alfons | Schmutzler, Rita K. | Olswold, Curtis | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Matsuo, Keitaro | Ito, Hidema | Iwata, Hiroji | Ishiguro, Junko | Wu, Anna H. | Tseng, Chiu-chen | Van Den Berg, David | Stram, Daniel O. | Teo, Soo Hwang | Yip, Cheng Har | Kang, Peter | Ikram, Mohammad Kamran | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Lee, Soo Chin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Wu, Pei-Ei | Hou, Ming-Feng | Yu, Jyh-Cherng | Shen, Chen-Yang | Blot, William | Cai, Qiuyin | Signorello, Lisa B. | Luccarini, Craig | Bayes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Hunter, David J. | Lindstrom, Sara | Dennis, Joe | Michailidou, Kyriaki | Bolla, Manjeet K. | Easton, Douglas F. | dos Santos Silva, Isabel | Fletcher, Olivia | Peto, Julian
Human Molecular Genetics  2015;24(10):2966-2984.
We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88–0.92]; P-value = 1.58 × 10−25). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08–1.17]; P-value = 7.89 × 10−09) and rs13294895 (OR = 1.09 [1.06–1.12]; P-value = 2.97 × 10−11). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06–1.18]; P-value = 2.77 × 10−05). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
doi:10.1093/hmg/ddv035
PMCID: PMC4406292  PMID: 25652398
11.  Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer 
Block, Matthew S. | Charbonneau, Bridget | Vierkant, Robert A. | Fogarty, Zachary | Bamlet, William R. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel | Pearce, Celeste Leigh | Schildkraut, Joellen | Menon, Usha | Kjaer, Susanne K. | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie T. | Hays, Laura E. | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James M. | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | Hogdall, Claus K. | Lundvall, Lene | Olson, Sara H. | Orlow, Irene | Paddock, Lisa E. | Rudolph, Anja | Eilber, Ursula | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K. | Ziolkowska-Seta, Izabela | Brinton, Louise A. | Yang, Hannah | Garcia-Closas, Montserrat | Despierre, Evelyn | Lambrechts, Sandrina | Vergote, Ignace | Walsh, Christine S. | Lester, Jenny | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Ziogas, Argyrios | Lubiński, Jan | Cybulski, Cezary | Menkiszak, Janusz | Jensen, Allan | Gayther, Simon A. | Ramus, Susan J. | Gentry-Maharaj, Aleksandra | Berchuck, Andrew | Wu, Anna H. | Pike, Malcolm C. | Van Den Berg, David | Terry, Kathryn L. | Vitonis, Allison F. | Ramirez, Starr M. | Rider, David N. | Knutson, Keith L. | Sellers, Thomas A. | Phelan, Catherine M. | Doherty, Jennifer A. | Johnatty, Sharon E. | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Kalli, Kimberly R. | Fridley, Brooke L. | Cunningham, Julie M. | Goode, Ellen L.
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
doi:10.1158/1055-9965.EPI-13-0962
PMCID: PMC4082406  PMID: 24740199
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
12.  Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer 
Block, Matthew S. | Charbonneau, Bridget | Vierkant, Robert A. | Fogarty, Zachary | Bamlet, William R. | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Rossing, Mary Anne | Cramer, Daniel | Pearce, Celeste Leigh | Schildkraut, Joellen | Menon, Usha | Kjaer, Susanne K. | Levine, Douglas A. | Gronwald, Jacek | Culver, Hoda Anton | Whittemore, Alice S. | Karlan, Beth Y. | Lambrechts, Diether | Wentzensen, Nicolas | Kupryjanczyk, Jolanta | Chang-Claude, Jenny | Bandera, Elisa V. | Hogdall, Estrid | Heitz, Florian | Kaye, Stanley B. | Fasching, Peter A. | Campbell, Ian | Goodman, Marc T. | Pejovic, Tanja | Bean, Yukie T. | Hays, Laura E. | Lurie, Galina | Eccles, Diana | Hein, Alexander | Beckmann, Matthias W. | Ekici, Arif B. | Paul, James | Brown, Robert | Flanagan, James M. | Harter, Philipp | du Bois, Andreas | Schwaab, Ira | Hogdall, Claus K. | Lundvall, Lene | Olson, Sara H. | Orlow, Irene | Paddock, Lisa E. | Rudolph, Anja | Eilber, Ursula | Dansonka-Mieszkowska, Agnieszka | Rzepecka, Iwona K. | Ziolkowska-Seta, Izabela | Brinton, Louise A. | Yang, Hannah | Garcia-Closas, Montserrat | Despierre, Evelyn | Lambrechts, Sandrina | Vergote, Ignace | Walsh, Christine S. | Lester, Jenny | Sieh, Weiva | McGuire, Valerie | Rothstein, Joseph H. | Ziogas, Argyrios | Lubiński, Jan | Cybulski, Cezary | Menkiszak, Janusz | Jensen, Allan | Gayther, Simon A. | Ramus, Susan J. | Gentry-Maharaj, Aleksandra | Berchuck, Andrew | Wu, Anna H. | Pike, Malcolm C. | Van Den Berg, David | Terry, Kathryn L. | Vitonis, Allison F. | Ramirez, Starr M. | Rider, David N. | Knutson, Keith L. | Sellers, Thomas A. | Phelan, Catherine M. | Doherty, Jennifer A. | Johnatty, Sharon E. | deFazio, Anna | Song, Honglin | Tyrer, Jonathan | Kalli, Kimberly R. | Fridley, Brooke L. | Cunningham, Julie M. | Goode, Ellen L.
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance—p < 2.5×10−5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41–2.35, p=4.13×10−6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56–0.82, p=2.33×10−5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77–0.92, p=6.49×10−5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26–0.73, p=4.56×10−4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
doi:10.1158/1055-9965.EPI-13-0962
PMCID: PMC4082406  PMID: 24740199
single nucleotide polymorphism; recurrence; survival; ovarian neoplasms
13.  A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer 
Molecular Oncology  2015;9(1):115-127.
Complex focal chromosomal rearrangements in cancer genomes, also called “firestorms”, can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER−) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p < 0.001). Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62–2.32) for BCSS, and of 1.49 (95%CI, 1.30–1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23–1.99) for ER+ and 1.55 (95%CI, 1.11–2.18) for ER− disease. None of the expression-based predictors were prognostic in the ER− subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical prognostication tool PREDICT significantly improved its performance. CAAI positive ovarian cancers (52%) also had worse prognosis: HRs of 1.3 (95%CI, 1.1–1.7) for PFS and 1.3 (95%CI, 1.1–1.6) for OS. This study validates CAAI as an independent predictor of survival in both ER+ and ER− breast cancer and reveals a significant prognostic value for CAAI in high-grade serous ovarian cancer.
Highlights
•The complex arm-wise aberration index (CAAI) captures focal complex DNA alterations.•Compared with other indices of genomic instability, CAAI adds unique information.•CAAI is validated as an independent prognostic marker in breast cancer (n = 1950).•Prognostic value of CAAI is independent of the 70- and 21-gene classifiers.•CAAI is a new independent prognostic marker in ovarian cancer.
doi:10.1016/j.molonc.2014.07.019
PMCID: PMC4286124  PMID: 25169931
Breast cancer; Ovarian cancer; Prognostic markers; Biomarker; Genomics; Genomic instability; DNA copy number; BCSS, Breast cancer specific survival; CAAI, Complex arm-wise aberration index; CNA, Copy number alterations; ER, Estrogen receptor; HR, Hazard ratio; HGSOC, High-grade serous ovarian cancer; MIP, Molecular inversion probe; OS, Overall survival; PFS, Progression free survival
14.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
15.  Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk 
Painter, Jodie N. | O'Mara, Tracy A. | Batra, Jyotsna | Cheng, Timothy | Lose, Felicity A. | Dennis, Joe | Michailidou, Kyriaki | Tyrer, Jonathan P. | Ahmed, Shahana | Ferguson, Kaltin | Healey, Catherine S. | Kaufmann, Susanne | Hillman, Kristine M. | Walpole, Carina | Moya, Leire | Pollock, Pamela | Jones, Angela | Howarth, Kimberley | Martin, Lynn | Gorman, Maggie | Hodgson, Shirley | De Polanco, Ma. Magdalena Echeverry | Sans, Monica | Carracedo, Angel | Castellvi-Bel, Sergi | Rojas-Martinez, Augusto | Santos, Erika | Teixeira, Manuel R. | Carvajal-Carmona, Luis | Shu, Xiao-Ou | Long, Jirong | Zheng, Wei | Xiang, Yong-Bing | Montgomery, Grant W. | Webb, Penelope M. | Scott, Rodney J. | McEvoy, Mark | Attia, John | Holliday, Elizabeth | Martin, Nicholas G. | Nyholt, Dale R. | Henders, Anjali K. | Fasching, Peter A. | Hein, Alexander | Beckmann, Matthias W. | Renner, Stefan P. | Dörk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Lambrechts, Diether | Coenegrachts, Lieve | Schrauwen, Stefanie | Amant, Frederic | Winterhoff, Boris | Dowdy, Sean C. | Goode, Ellen L. | Teoman, Attila | Salvesen, Helga B. | Trovik, Jone | Njolstad, Tormund S. | Werner, Henrica M.J. | Ashton, Katie | Proietto, Tony | Otton, Geoffrey | Tzortzatos, Gerasimos | Mints, Miriam | Tham, Emma | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Hopper, John L. | Southey, Melissa C. | Ekici, Arif B. | Ruebner, Matthias | Johnson, Nicola | Peto, Julian | Burwinkel, Barbara | Marme, Frederik | Brenner, Hermann | Dieffenbach, Aida K. | Meindl, Alfons | Brauch, Hiltrud | Lindblom, Annika | Depreeuw, Jeroen | Moisse, Matthieu | Chang-Claude, Jenny | Rudolph, Anja | Couch, Fergus J. | Olson, Janet E. | Giles, Graham G. | Bruinsma, Fiona | Cunningham, Julie M. | Fridley, Brooke L. | Børresen-Dale, Anne-Lise | Kristensen, Vessela N. | Cox, Angela | Swerdlow, Anthony J. | Orr, Nicholas | Bolla, Manjeet K. | Wang, Qin | Weber, Rachel Palmieri | Chen, Zhihua | Shah, Mitul | French, Juliet D. | Pharoah, Paul D.P. | Dunning, Alison M. | Tomlinson, Ian | Easton, Douglas F. | Edwards, Stacey L. | Thompson, Deborah J. | Spurdle, Amanda B.
Human Molecular Genetics  2014;24(5):1478-1492.
Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10−14, odds ratio = 0.86, 95% confidence interval = 0.82–0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
doi:10.1093/hmg/ddu552
PMCID: PMC4321445  PMID: 25378557
16.  Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome 
Charbonneau, Bridget | Moysich, Kirsten B. | Kalli, Kimberly R. | Oberg, Ann L. | Vierkant, Robert A. | Fogarty, Zachary C. | Block, Matthew S. | Maurer, Matthew J. | Goergen, Krista M. | Fridley, Brooke L. | Cunningham, Julie M. | Rider, David N. | Preston, Claudia | Hartmann, Lynn C. | Lawrenson, Kate | Wang, Chen | Tyrer, Jonathan | Song, Honglin | deFazio, Anna | Johnatty, Sharon E. | Doherty, Jennifer A. | Phelan, Catherine M. | Sellers, Thomas A. | Ramirez, Starr M. | Vitonis, Allison F. | Terry, Kathryn L. | Van Den Berg, David | Pike, Malcolm C. | Wu, Anna H. | Berchuck, Andrew | Gentry-Maharaj, Aleksandra | Ramus, Susan J. | Diergaarde, Brenda | Shen, Howard | Jensen, Allan | Menkiszak, Janusz | Cybulski, Cezary | Lubiński, Jan | Ziogas, Argyrios | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Lester, Jenny | Walsh, Christine | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Garcia-Closas, Montserrat | Yang, Hannah | Brinton, Louise A. | Spiewankiewicz, Beata | Rzepecka, Iwona K. | Dansonka-Mieszkowska, Agnieszka | Seibold, Petra | Rudolph, Anja | Paddock, Lisa E. | Orlow, Irene | Lundvall, Lene | Olson, Sara H. | Hogdall, Claus K. | Schwaab, Ira | du Bois, Andreas | Harter, Philipp | Flanagan, James M. | Brown, Robert | Paul, James | Ekici, Arif B. | Beckmann, Matthias W. | Hein, Alexander | Eccles, Diana | Lurie, Galina | Hays, Laura E. | Bean, Yukie T. | Pejovic, Tanja | Goodman, Marc T. | Campbell, Ian | Fasching, Peter A. | Konecny, Gottfried | Kaye, Stanley B. | Heitz, Florian | Hogdall, Estrid | Bandera, Elisa V. | Chang-Claude, Jenny | Kupryjanczyk, Jolanta | Wentzensen, Nicolas | Lambrechts, Diether | Karlan, Beth Y. | Whittemore, Alice S. | Culver, Hoda Anton | Gronwald, Jacek | Levine, Douglas A. | Kjaer, Susanne K. | Menon, Usha | Schildkraut, Joellen M. | Pearce, Celeste Leigh | Cramer, Daniel W. | Rossing, Mary Anne | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A. | Ness, Roberta B. | Odunsi, Kunle | Sucheston, Lara E. | Knutson, Keith L. | Goode, Ellen L.
Cancer immunology research  2014;2(4):332-340.
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22-1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17-1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.19-1.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17-1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54-0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
doi:10.1158/2326-6066.CIR-13-0136
PMCID: PMC4000890  PMID: 24764580
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
17.  Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome 
Charbonneau, Bridget | Moysich, Kirsten B. | Kalli, Kimberly R. | Oberg, Ann L. | Vierkant, Robert A. | Fogarty, Zachary C. | Block, Matthew S. | Maurer, Matthew J. | Goergen, Krista M. | Fridley, Brooke L. | Cunningham, Julie M. | Rider, David N. | Preston, Claudia | Hartmann, Lynn C. | Lawrenson, Kate | Wang, Chen | Tyrer, Jonathan | Song, Honglin | deFazio, Anna | Johnatty, Sharon E. | Doherty, Jennifer A. | Phelan, Catherine M. | Sellers, Thomas A. | Ramirez, Starr M. | Vitonis, Allison F. | Terry, Kathryn L. | Van Den Berg, David | Pike, Malcolm C. | Wu, Anna H. | Berchuck, Andrew | Gentry-Maharaj, Aleksandra | Ramus, Susan J. | Diergaarde, Brenda | Shen, Howard | Jensen, Allan | Menkiszak, Janusz | Cybulski, Cezary | Lubiński, Jan | Ziogas, Argyrios | Rothstein, Joseph H. | McGuire, Valerie | Sieh, Weiva | Lester, Jenny | Walsh, Christine | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Garcia-Closas, Montserrat | Yang, Hannah | Brinton, Louise A. | Spiewankiewicz, Beata | Rzepecka, Iwona K. | Dansonka-Mieszkowska, Agnieszka | Seibold, Petra | Rudolph, Anja | Paddock, Lisa E. | Orlow, Irene | Lundvall, Lene | Olson, Sara H. | Hogdall, Claus K. | Schwaab, Ira | du Bois, Andreas | Harter, Philipp | Flanagan, James M. | Brown, Robert | Paul, James | Ekici, Arif B. | Beckmann, Matthias W. | Hein, Alexander | Eccles, Diana | Lurie, Galina | Hays, Laura E. | Bean, Yukie T. | Pejovic, Tanja | Goodman, Marc T. | Campbell, Ian | Fasching, Peter A. | Konecny, Gottfried | Kaye, Stanley B. | Heitz, Florian | Hogdall, Estrid | Bandera, Elisa V. | Chang-Claude, Jenny | Kupryjanczyk, Jolanta | Wentzensen, Nicolas | Lambrechts, Diether | Karlan, Beth Y. | Whittemore, Alice S. | Culver, Hoda Anton | Gronwald, Jacek | Levine, Douglas A. | Kjaer, Susanne K. | Menon, Usha | Schildkraut, Joellen M. | Pearce, Celeste Leigh | Cramer, Daniel W. | Rossing, Mary Anne | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A. | Ness, Roberta B. | Odunsi, Kunle | Sucheston, Lara E. | Knutson, Keith L. | Goode, Ellen L.
Cancer immunology research  2014;2(4):332-340.
The presence of regulatory T cells (Tregs) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag SNPs in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR=1.42, 95% CI: 1.22–1.64; p=5.7 × 10−6], rs791587 [HR=1.36, 95% CI:1.17–1.57; p=6.2 × 10−5], rs2476491 [HR=1.40, 95% CI: 1.191.64; p=5.6 × 10−5], and rs10795763 [HR=1.35, 95% CI: 1.17–1.57; p=7.9 × 10−5], and for clear cell carcinoma and CTLA4 SNP rs231775 [HR=0.67, 95% CI: 0.54–0.82; p=9.3 × 10−5] after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs appear to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid EOC.
doi:10.1158/2326-6066.CIR-13-0136
PMCID: PMC4000890  PMID: 24764580
clear cell; endometrioid; gynecologic neoplasms; single nucleotide polymorphism
18.  The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length 
Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
doi:10.1093/jnci/dju267
PMCID: PMC4196080  PMID: 25231748
19.  Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer 
Milne, Roger L. | Goode, Ellen L. | García-Closas, Montserrat | Couch, Fergus J. | Severi, Gianluca | Hein, Rebecca | Fredericksen, Zachary | Malats, Núria | Zamora, M. Pilar | Pérez, Jose Ignacio Arias | Benítez, Javier | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Cox, Angela | Brock, Ian W. | Elliot, Graeme | Cross, Simon S. | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Rahman, Nazneen | Shen, Chen-Yang | Yu, Jyh-Cherng | Huang, Chiun-Sheng | Hou, Ming-Feng | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Lambrechts, Diether | Yesilyurt, Betül T. | Floris, Giuseppe | Leunen, Karin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Chang-Claude, Jenny | Wang-Gohrke, Shan | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Giles, Graham G. | Baglietto, Laura | John, Esther M. | Miron, Alexander | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Figueroa, Jonine D. | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Rogov, Yuri I. | Fasching, Peter A. | Bayer, Christian M. | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Meindl, Alfons | Heil, Joerg | Bartram, Claus R. | Schmutzler, Rita K. | Thomas, Gilles D. | Hoover, Robert N. | Fletcher, Olivia | Gibson, Lorna J. | Silva, Isabel dos Santos | Peto, Julian | Nickels, Stefan | Flesch-Janys, Dieter | Anton-Culver, Hoda | Ziogas, Argyrios | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Schmidt, Marjanka K. | Broeks, Annegien | Van ‘t Veer, Laura J. | Tollenaar, Rob A.E.M. | Pharoah, Paul D.P. | Dunning, Alison M. | Pooley, Karen A. | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Kraft, Peter | Lindstrom, Sara | Chen, Xiaoqing | Beesley, Jonathan | Hamann, Ute | Harth, Volker | Justenhoven, Christina | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje | Hollestelle, Antoinette | Oldenburg, Rogier A. | Tilanus-Linthorst, Madeleine | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Farahtdinova, Albina | Olson, Janet E. | Wang, Xianshu | Humphreys, Manjeet K. | Wang, Qin | Chenevix-Trench, Georgia | Easton, Douglas F.
Background
The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
Methods
Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.
Results
For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7).
Conclusion
5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer.
Impact
Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
doi:10.1158/1055-9965.EPI-11-0569
PMCID: PMC4164116  PMID: 21795498
Breast cancer; SNP; susceptibility; disease subtypes
20.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
21.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
22.  Associations between hormone receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study 
The lancet oncology  2013;14(9):853-862.
Background
Ovarian cancer is a lethal disease comprised of distinct histopathological types. There are few established biomarkers of ovarian cancer prognosis, in part because subtype-specific associations may have been obscured in studies combining all subtypes. We examined whether progesterone receptor (PR) and estrogen receptor (ER) protein expression were associated with subtype-specific survival in the international Ovarian Tumor Tissue Analysis (OTTA) consortium.
Methods
PR and ER were assessed by central immunohistochemical analysis of tissue microarrays for 2933 women with invasive epithelial ovarian cancer from 12 study sites. Negative, weak, and strong expression were defined as positive staining in <1%, 1–50%, and ≥50% of tumor cell nuclei, respectively. Hazard ratios (HRs) for ovarian cancer death were estimated using Cox regression stratified by site and adjusted for age, stage, and grade.
Results
PR expression was associated with improved survival for endometrioid (EC; p<0·0001) and high-grade serous carcinoma (HGSC; p=0·0006), and ER expression was associated with improved EC survival (p<0·0001); no significant associations were found for mucinous, clear cell, or low-grade serous carcinoma. EC patients with hormone receptor (PR and/or ER) positive (weak or strong) versus negative tumors had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·33; 95% CI, 0·21–0·51; p<0·0001). HGSC patients with strong versus weak or negative tumor PR expression had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·71; 95% CI, 0·55–0·91; p=0·0061).
Interpretation
PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to determine whether hormone receptor status predicts response to endocrine therapy, and can guide personalized treatment for ovarian cancer.
Funding
Carraressi Foundation, US National Institutes of Health, National Health and Medical Research Council of Australia, UK National Institute for Health Research, and others.
doi:10.1016/S1470-2045(13)70253-5
PMCID: PMC4006367  PMID: 23845225
23.  Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions 
Schoeps, Anja | Rudolph, Anja | Seibold, Petra | Dunning, Alison M. | Milne, Roger L. | Bojesen, Stig E. | Swerdlow, Anthony | Andrulis, Irene | Brenner, Hermann | Behrens, Sabine | Orr, Nicholas | Jones, Michael | Ashworth, Alan | Li, Jingmei | Cramp, Helen | Connley, Dan | Czene, Kamila | Darabi, Hatef | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Knight, Julia | Glendon, Gord | Mulligan, Anna M. | Dumont, Martine | Severi, Gianluca | Baglietto, Laura | Olson, Janet | Vachon, Celine | Purrington, Kristen | Moisse, Matthieu | Neven, Patrick | Wildiers, Hans | Spurdle, Amanda | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Hamann, Ute | Ko, Yon-Dschun | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Malats, Núria | Arias Perez, JoséI. | Benítez, Javier | Flyger, Henrik | Nordestgaard, Børge G. | Truong, Théresè | Cordina-Duverger, Emilie | Menegaux, Florence | Silva, Isabel dos Santos | Fletcher, Olivia | Johnson, Nichola | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Braaf, Linde | Atsma, Femke | van den Broek, Alexandra J. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Cox, Angela | Simard, Jacques | Giles, Graham G. | Lambrechts, Diether | Mannermaa, Arto | Brauch, Hiltrud | Guénel, Pascal | Peto, Julian | Fasching, Peter A. | Hopper, John | Flesch-Janys, Dieter | Couch, Fergus | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Schmidt, Marjanka K. | Hall, Per | Easton, Douglas F. | Chang-Claude, Jenny
Genetic epidemiology  2013;38(1):84-93.
Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.
doi:10.1002/gepi.21771
PMCID: PMC3995140  PMID: 24248812
breast cancer risk; gene-environment interaction; polymorphisms; body mass index; case-control study
24.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | 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 | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729

Results 1-25 (98)