Citations 26
Germline Mutation in BRCA1 or BRCA2 and Ten-Year Survival for Women Diagnosed with Epithelial Ovarian Cancer
Reis, Francisco José Cândido dos , Song, Honglin , Goode, Ellen L. , Cunningham, Julie M. , Alsop, Kathryn , Dicks, Ed , Harrington, Patricia, Ramus, Susan J. , Fazio, Anna de , Mitchell, Gillian, Fereday, Sián , Bolton, Kelly L. , Gourley, Charlie , Michie, Caroline O. , Lester, Jenny, Walsh, Christine , Cass, Ilana, Olsson, Håkan , Gore, Martin, Benı́tez, Javier , García, María J. , Andrulis, Irene L. , Mulligan, Anna Marie , Glendon, Gord , Blanco, Ignacio , Lázaro, Conxi , Whittemore, Alice S. , McGuire, Valerie , Sieh, Weiva , Montagna, Marco , Alducci, Elisa, Sadetzki, Siegal , Chetrit, Angela , Kwong, Ava , Kjær, Susanne K. , Jensen, Allan , Høgdall, Estrid , Daly, Mary B., Greene, Mark H. , Mai, Phuong L., Loud, Jennifer T. , Moysich, Kirsten, Lambrechts, Diether , Ellis, Steve, Frost, Debra, Brenton, James D. , Easton, Douglas F. , Antoniou, Antonis C. , Chenevix‐Trench, Georgia , Gayther, Simon A. , Bowtell, David D.L. , DeFazio, Anna , Thorne, Heather , Lambrechts, Diether , Fridley, Brooke L. , Larson, Melissa C. , Karlan, Beth Y. , Neuhausen, Susan L. , Nussbaum, Robert L. , Mai, Phuong L., Toland, Amanda Ewart , Ellis, Steve, Tischkowitz, Marc D. , Pharoah, Paul D.P. , Lambrechts, Diether , Kjaer, Susanne K , Ramus, Susan J , Jensen, Allan , Brenton, James D , Moysich, Kirsten , Lambrechts, Diether , Sieh, Weiva , Benitez, Javier , Lazaro, Conxi , Montagna, Marco , Chenevix-Trench, Georgia , Høgdall, Estrid , Bolton, Kelly L , Bowtell, David D , Fereday, Sian , Alsop, Kathryn , Kwong, Ava
Clinical Cancer Research | November 15, 2014 | Volume: 21 | Issue: 3 | Pages: 652-657
Abstract Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 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 Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies.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 analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 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. Clin Cancer Res; 21(3); 652–7. ©2014 AACR.
Candidate Genetic Modifiers for Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
Peterlongo, Paolo , Chang-Claude, Jenny, Moysich, Kirsten B., 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. , Baan, Frederieke H. van der , Spurdle, Amanda B. , Walker, Logan C. , Lose, Felicity , Maia, Ana-Teresa , Montagna, Marco , Matricardi, Laura , Lubiński, Jan , Jakubowska, Anna , Gómez, E. , Olopade, Olufunmilayo I., Nathanson, Katherine L. , Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Oršulić, Sandra , Lester, Jenny, Chung, Wendy K., Miron, Alex, Southey, Melissa C. , Goldgar, David E., Janavičius, Ramūnas , Dorfling, Cecilia M., Rensburg, Elizabeth J. van , Ding, Yuan Chun , Neuhausen, Susan L., Hansen, Thomas van Overeem , Gerdes, Anne‐Marie , Ejlertsen, Bent , Jønson, Lars, Osório, Ana , Martínez-Bouzas, Cristina, Benı́tez, Javier , Conway, Edye E., Blazer, Kathleen R. , Weitzel, Jeffrey N. , Manoukian, Siranoush , Peissel, Bernard , Zaffaroni, Daniela , Scuvera, Giulietta, Barile, Monica, Ficarazzi, Filomena , Mariette, Frédérique, Fortuzzi, Stefano , Viel, Alessandra , Giannini, Giuseppe , Papi, Laura , Martayan, Aline , Tibiletti, Maria Grazia , Radice, Paolo , Vratimos, Athanassios, Fostira, Florentia, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D. Gareth , Frost, Debra, Eccles, Diana , Brady, Angela, Adlard, Julian , Walker, Lisa, Izatt, Louise , Side, Lucy E., Rogers, Mark T., Porteous, Mary, Morrison, Patrick J., Platte, Radka, Davidson, Rosemarie, Hodgson, Shirley V. , Ellis, Steve, Cole, Trevor, EMBRACE, on behalf of, Claes, Kathleen , Maerken, Tom Van, Meindl, Alfons , Gehrig, Andrea, Sutter, Christian , Engel, Christoph , Niederacher, Dieter , Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina , Varon-Mateeva, Raymonda, Wappenschmidt, Barbara , Wang-Gohrke, Shan, Paillerets, Brigitte Bressac–de , Buecher, Bruno , Delnatte, Capucine, Houdayer, Claude , Coupier, Isabelle, Barjhoux, Laure, Venat‐Bouvet, Laurence , Boutry‐Kryza, Nadia, Sinilnikova, Olga M., Caron, Olivier , Mazoyer, Sylvie , Belotti, Muriel, Collaborators, on behalf of GEMO Study, Piedmonte, Marion, Friedländer, Michael , Rodriguez, Gustavo C., Copeland, Larry J. , Hoya, Miguel de la , Segura, Pedro Pérez, Nevanlinna, Heli , Aittomäki, Kristiina, Os, Theo A.M. van, Meijers-Heijboer, Hanne E.J., Hout, Annemarie H. van der, Hoogerbrugge, Nicoline, Ausems, Margreet G.E.M. , Doorn, Helena C. van , Collée, Margriet , HEBON, on behalf of, Oláh, Edith , Dı́ez, Orland , Blanco, Ignacio , Lázaro, Conxi , Brunet, Joan , Feliubadaló, Lídia , Cybulski, Cezary, Durda, Katarzyna, Jaworska–Bieniek, Katarzyna, Sukiennicki, Grzegorz, Arason, Aðalgeir , Chiquette, Jocelyne , Teixeira, Manuel R. , Olswold, Curtis, Lindor, Noralane M. , Offit, Kenneth, Corines, Marina, Jacobs, Lauren , Robson, Mark E. , Zhang, Liying , Vijai, Joseph , 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., Bojesen, Anders , Pedersen, Inge Søkilde , Thomassen, Mads , Jensen, Uffe Birk , Laitman, Yael , Rantala, Johanna, Wachenfeldt, Anna von , Ehrencrona, Hans , Askmalm, Marie Stenmark, Borg, Åke , Kuchenbaecker, Karoline B., McGuffog, Lesley, Barrowdale, Daniel , Healey, Sue, Lee, Andrew , Chenevix‐Trench, Georgia , Investigators, on behalf of KConFab, Antoniou, Antonis C. , Friedman, Eitan , Durocher, Francine , Olopade, Olufunmilayo I. , Hoogerbrugge, Nicoline , Thorne, Heather , Stenmark‐Askmalm, Marie , Wang, Xianshu , Chang‐Claude, Jenny, Moysich, Kirsten B. , Rudolph, Anja , Nussbaum, Robert L. , Domchek, Susan M. , Arun, Banu , By, Karlan, Chung, Wendy K. , Buys, Saundra S. , Garber, Judy E. , Cook, Jackie A , Tischkowitz, Marc D. , Barwell, Julian , Kennedy, Michael John , Ellis, Steve, EMBRACE, on behalf of, Godwin, Andrew K. , Meindl, Alfons , Steinemann, Doris , Arnold, Norbert , Wang-Gohrke, Shan, Stoppa‐Lyonnet, Dominique , Damiola, Francesca , Golmard, Lisa , Pujol, Pascal , Collaborators, on behalf of GEMO Study, Meijers‐Heijboer, Hanne , Vreeswijk, Maaike P.G. , Hoogerbrugge, Nicoline, HEBON, on behalf of, Gronwald, Jacek , Couch, Fergus J. , Szabo, Csilla I. , Singer, Christian F , Mai, Phuong L., Toland, Amanda Ewart , Pharoah, Paul D.P. , Investigators, on behalf of KConFab, Nevanlinna, H , Peterlongo, Paolo , Rennert, Gad , Spurdle, Amanda B , Teixeira, Manuel R , van Rensburg, Elizabeth J , Eccles, Diana , Moysich, Kirsten , de la Hoya, Miguel , Diez, Orland , Radice, Paolo , Weitzel, Jeffrey N , Claes, Kathleen B M , Adlard, Julian , Brunet, Joan , Eeles, Rosalind A , Ehrencrona, Hans , Evans, D Gareth , Joseph, Vijai , Matricardi, Laura , Olopade, Olufunmilayo I , Southey, Melissa C , Jakubowska, Anna , Schmidt, Marjanka K , Nathanson, Katherine L , Friedlander, Michael , Arason, Adalgeir , Barrowdale, Daniel , Benitez, Javier , Engel, Christoph , Lazaro, Conxi , Montagna, Marco , Robson, Mark , Viel, Alessandra , Simard, Jacques , Chenevix-Trench, Georgia , Feliubadaló, Lidia , Gómez-García, Encarna B , Hansen, Thomas van Overeem , Manoukian, Siranoush , Lubinski, Jan , Rhiem, Kerstin
Cancer Epidemiology, Biomarkers & Prevention | October 22, 2014 | Volume: 24 | Issue: 1 | Pages: 308-316
Abstract 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 nongenetic 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 and 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. Cancer Epidemiol Biomarkers Prev; 24(1); 308–16. ©2014 AACR.
Consortium analysis of gene and gene–folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk
Kelemen, Linda E. , Terry, Kathryn L. , Goodman, Marc T. , Webb, Penelope M. , McGuire, Valerie , Rossing, Mary Anne, Wang, Qinggang , Dicks, Ed , Song, Honglin , Kupryjańczyk, Jolanta , Dansonka‐Mieszkowska, Agnieszka , Plisiecka-Hałasa, Joanna, Timorek, Agnieszka, Menon, Usha , Gayther, Simon A. , Ramus, Susan J. , Narod, Steven A., McLaughlin, John R., Glasspool, Rosalind , Lubiński, Jan , Jakubowska, Anna , Kiemeney, Lambertus A. , Massuger, Leon F.A.G. , Altena, Anne M. van , Aben, Katja K.H. , Olson, Sara H. , Orlow, Irene , Levine, Douglas A. , Bisogna, Maria, Southey, Melissa C. , Bruinsma, Fiona , Kjær, Susanne K. , Høgdall, Estrid , Jensen, Allan , Høgdall, Claus , Lundvall, Lene, Engelholm, Svend‐Aage, Harter, Philipp , Schwaab, Ira, Nevanlinna, Heli , Pelttari, Liisa M. , Leminen, Arto, Thompson, Pamela J., Lurie, Galina, Lambrechts, Diether , Nieuwenhuysen, Els Van , Lambrechts, Sandrina, Vergote, Ignace , Beesley, Jonathan, Investigators, AOCS Study Group/ACS, Fasching, Peter A. , Beckmann, Matthias W. , Hein, Alexander , Ekici, Arif B. , Wu, Anna H. , Pearce, Celeste Leigh, Pike, Malcolm C., Chang‐Claude, Jenny , Dörk, Thilo , Hillemanns, Peter , Runnebaum, Ingo B. , Bogdanova, Natalia , Antonenkova, Natalia, Odunsi, Kunle , Edwards, Robert P., Kelley, Joseph L., Ness, Roberta B., Walsh, Christine , Lester, Jenny, Oršulić, Sandra , Vierkant, Robert A. , Cunningham, Julie M. , Wu, Xifeng , Lu, Karen H., Hildebrandt, Michelle A.T., Weber, Rachel Palmieri , Iversen, Edwin S., Tworoger, Shelley S. , Salvesen, Helga B., Tangen, Ingvild L. , Bean, Yukie T., Kellar, Melissa, Wentzensen, Nicolas , Brinton, Louise A. , Lissowska, Jolanta , García‐Closas, Montserrat , Campbell, Ian , Eccles, Diana , Whittemore, Alice S. , Sieh, Weiva , Rothstein, Joseph H. , Phelan, Catherine M., Moysich, Kirsten B., Goode, Ellen L. , Schildkraut, Joellen M. , Sellers, Thomas A. , Le, Nhu D. , Lu, Karen H. , Zheng, Wei , Lambrechts, Diether , Bandera, Elisa V. , Tyrer, Jonathan P. , Gentry‐Maharaj, Aleksandra , Risch, Harvey A. , McLaughlin, John R., Siddiqui, Nadeem , Paul, James , Carty, Karen , Gronwald, Jacek , Cybulski, Cezary , Cramer, Daniel W. , Giles, Graham G. , Heitz, Florian , Bois, Andreas du , Bützow, Ralf C. , Wilkens, Lynne R. , Beesley, Jonathan, Investigators, AOCS Study Group/ACS, Doherty, Jennifer A. , Stram, Daniel O. , Rudolph, Anja , Dürst, Matthias , Modugno, Francesmary , Karlan, Beth Y. , Fridley, Brooke L. , Liang, Dong , Hildebrandt, Michelle A.T. , Poole, Elizabeth M. , Krakstad, Camilla , Bjørge, Line , Pejovic, Tanja B. , Anton‐Culver, Hoda , Ziogas, Argyrios , Berchuck, Andrew , Pharoah, Paul D.P. , Brooks‐Wilson, Angela , Cook, Linda S. , Pelttari, L M , Nevanlinna, H , Dörk, Thilo , Lambrechts, Diether , Kiemeney, Lambertus A , Kjaer, Susanne K , Ramus, Susan J , Tworoger, Shelley S , Webb, Penelope M , Hein, Alexander , Hillemanns, Peter , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Moysich, Kirsten , Orlow, Irene , Lissowska, Jolanta , Campbell, Ian G , Southey, Melissa C , Glasspool, Rosalind , Jakubowska, Anna , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , García-Closas, Montserrat , Ekici, Arif B , Bogdanova, Natalia V , Zheng, Wei , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T
Molecular Nutrition & Food Research | July 28, 2014 | Volume: 58 | Issue: 10 | Pages: 2023-2035
ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
Variation in NF-κB Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer
Block, Matthew S. , Charbonneau, Bridget, Vierkant, Robert A. , Fogarty, Zachary C. , Bamlet, William R. , Chenevix-Trench, Georgia, AOCS, for, Group, /ACS, Rossing, Mary Anne, Cramer, Daniel, Pearce, Celeste Leigh, Schildkraut, Joellen, Menon, Usha , Kjær, Susanne K. , Levine, Douglas A. , Culver, Hoda Anton, Whittemore, Alice S. , Lambrechts, Diether , Wentzensen, Nicolas , Kupryjańczyk, Jolanta , Chang‐Claude, Jenny , Bandera, Elisa V. , Høgdall, Estrid , Heitz, Florian , Kaye, Stanley B., Fasching, Peter A. , Campbell, Ian , Goodman, Marc T. , 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 , Schwaab, Ira, Høgdall, Claus , Lundvall, Lene, Olson, Sara H. , Orlow, Irene , Paddock, Lisa E. , Eilber, Ursula, Dansonka‐Mieszkowska, Agnieszka , Rzepecka, Iwona K. , Ziółkowska-Seta, Izabela, Brinton, Louise A. , García‐Closas, Montserrat , Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace , Walsh, Christine , Lester, Jenny, Sieh, Weiva , McGuire, Valerie , Rothstein, Joseph H. , Ziogas, Argyrios, Lubiński, Jan , Menkiszak, Janusz , Jensen, Allan , Gayther, Simon A. , Ramus, Susan J. , Wu, Anna H. , Pike, Malcolm C. , Terry, Kathryn L. , Vitonis, Allison F., Ramirez, Starr M., Rider, David N., Knutson, Keith L. , Sellers, Thomas A. , Phelan, Catherine M., Johnatty, Sharon E., DeFazio, Anna , Song, Honglin , Kalli, Kimberly R., Cunningham, Julie M. , Goode, Ellen L. , Chenevix‐Trench, Georgia , Lambrechts, Diether , Pharoah, Paul D.P. , Chenevix-Trench, Georgia, AOCS, for, Group, /ACS, Gronwald, Jacek , Karlan, Beth Y. , Pejovic, Tanja B. , Bois, Andreas du , Rudolph, Anja , Yang, Hannah , Lester, Jenny, Cybulski, Cezary , Gentry‐Maharaj, Aleksandra , Berchuck, Andrew , Berg, David Van Den , Knutson, Keith L. , Doherty, Jennifer A. , Tyrer, Jonathan P. , Fridley, Brooke L. , Fazio, Anna de , Lambrechts, Diether , Kjaer, Susanne K , Ramus, Susan J , Hein, Alexander , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Orlow, Irene , Campbell, Ian G , Bamlet, William R , Menkiszak, Janusz , Brown, Robert , Fogarty, Zachary C , Flanagan, James M , Heitz, Florian , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , García-Closas, Montserrat , Ekici, Arif B , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T , Bandera, Elisa V.
Cancer Epidemiology, Biomarkers & Prevention | April 17, 2014 | Volume: 23 | Issue: 7 | Pages: 1421-1427
Abstract Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-κB (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 caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41–2.35; P = 4.13 × 10−6] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) 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 TNF receptor–associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77–0.92; P = 6.49 × 10−5) and phospholipase C, gamma 1 (PLCG1) 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. Cancer Epidemiol Biomarkers Prev; 23(7); 1421–7. ©2014 AACR.
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. , Goergen, Krista M., Cunningham, Julie M. , Rider, David N., Hartmann, Lynn C. , Lawrenson, Kate , Wang, Chen , Song, Honglin , DeFazio, Anna , Johnatty, Sharon E., Phelan, Catherine M., Sellers, Thomas A. , Ramirez, Starr M., Vitonis, Allison F., Terry, Kathryn L. , Pike, Malcolm C. , Wu, Anna H. , Ramus, Susan J. , Diergaarde, Brenda , Shen, Howard C., Jensen, Allan , Menkiszak, Janusz , Lubiński, Jan , Rothstein, Joseph H. , McGuire, Valerie , Sieh, Weiva , Lester, Jenny, Walsh, Christine , Vergote, Ignace , Lambrechts, Sandrina, Despierre, Evelyn, García‐Closas, Montserrat , Brinton, Louise A. , Śpiewankiewicz, Beata, Rzepecka, Iwona K. , Dansonka‐Mieszkowska, Agnieszka , Paddock, Lisa E. , Orlow, Irene , Lundvall, Lene, Olson, Sara H. , Høgdall, Claus , Schwaab, Ira, Harter, Philipp , Flanagan, James M. , Brown, Robert , Ekici, Arif B. , Beckmann, Matthias W. , Hein, Alexander , Eccles, Diana , Lurie, Galina, Hays, Laura E., Bean, Yukie T., Goodman, Marc T. , Campbell, Ian , Fasching, Peter A. , Konecny, Gottfried E. , Kaye, Stanley B., Heitz, Florian , Høgdall, Estrid , Chang‐Claude, Jenny , Kupryjańczyk, Jolanta , Wentzensen, Nicolas , Lambrechts, Diether , Whittemore, Alice S. , Culver, Hoda Anton, Levine, Douglas A. , Kjær, Susanne K. , Menon, Usha , Schildkraut, Joellen M. , Pearce, Celeste Leigh, Rossing, Mary Anne, Chenevix‐Trench, Georgia , group, for the AOCS, ACS, Gayther, Simon A. , Ness, Roberta B., Odunsi, Kunle , Sucheston, Lara E., Knutson, Keith L. , Goode, Ellen L. , Lambrechts, Diether , Maurer, Matthew J. , Fridley, Brooke L. , Preston, Claudia C. , Tyrer, Jonathan P. , Doherty, Jennifer A. , Berg, David Van Den , Berchuck, Andrew , Gentry‐Maharaj, Aleksandra , Cybulski, Cezary , Ziogas, Argyrios , Yang, Hannah , Seibold, Petra , Rudolph, Anja , Bois, Andreas du , Paul, James , Pejovic, Tanja B. , Bandera, Elisa V. , Karlan, Beth Y. , Gronwald, Jacek , Cramer, Daniel W. , group, for the AOCS, ACS, Pharoah, Paul D.P. , Knutson, Keith L. , Fazio, Anna de , Lambrechts, Diether , Kjaer, Susanne K , Ramus, Susan J , Hein, Alexander , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Lawrenson, Kate , Moysich, Kirsten , Orlow, Irene , Wang, Chen , Campbell, Ian G , Menkiszak, Janusz , Brown, Robert , Fogarty, Zachary C , Flanagan, James M , Heitz, Florian , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , García-Closas, Montserrat , Ekici, Arif B , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K , Diergaarde, Brenda , Lubinski, Jan , Goodman, Marc T
Cancer Immunology Research | January 27, 2014 | Volume: 2 | Issue: 4 | Pages: 332-340
Abstract The presence of regulatory T cells (Treg) 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 single-nucleotide polymorphisms (SNP) 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% confidence interval (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 seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332–40. ©2014 AACR.
Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome
White, Kristin L., Vierkant, Robert A. , Fogarty, Zachary C. , Charbonneau, Bridget, Block, Matthew S. , Chenevix‐Trench, Georgia , group;, for AOCS/ACS, Rossing, Mary Anne, Pearce, Celeste Leigh, Schildkraut, Joellen M. , Menon, Usha , Kjær, Susanne K. , Levine, Douglas A. , Culver, Hoda Anton, Whittemore, Alice S. , Lambrechts, Diether , Wentzensen, Nicolas , Kupryjańczyk, Jolanta , Chang‐Claude, Jenny , Bandera, Elisa V. , Høgdall, Estrid , Heitz, Florian , Kaye, Stanley B., Fasching, Peter A. , Campbell, Ian , Goodman, Marc T. , Bean, Yukie T., Lurie, Galina, Eccles, Diana , Hein, Alexander , Beckmann, Matthias W. , Ekici, Arif B. , Brown, Robert , Flanagan, James M. , Harter, Philipp , Schwaab, Ira, Høgdall, Claus , Lundvall, Lene, Olson, Sara H. , Orlow, Irene , Paddock, Lisa E. , Rudolph, Anja , Eilber, Ursula, Dansonka‐Mieszkowska, Agnieszka , Rzepecka, Iwona K. , Ziółkowska-Seta, Izabela, Brinton, Louise A. , García‐Closas, Montserrat , Despierre, Evelyn, Lambrechts, Sandrina, Vergote, Ignace , Walsh, Christine , Lester, Jenny, Sieh, Weiva , McGuire, Valerie , Rothstein, Joseph H. , Lubiński, Jan , Menkiszak, Janusz , Jensen, Allan , Gayther, Simon A. , Ramus, Susan J. , Wu, Anna H. , Pike, Malcolm C. , DenBerg, David Van, Terry, Kathryn L. , Vitonis, Allison F., Johnatty, Sharon E., DeFazio, Anna , Song, Honglin , Sellers, Thomas A. , Phelan, Catherine M., Kalli, Kimberly R., Cunningham, Julie M. , Goode, Ellen L. , Lambrechts, Diether , Pharoah, Paul D.P. , group;, for AOCS/ACS, Cramer, Daniel W. , Gronwald, Jacek , Karlan, Beth Y. , Pejovic, Tanja B. , Paul, James , Bois, Andreas du , Yang, Hannah , Ziogas, Argyrios , Cybulski, Cezary , Gentry‐Maharaj, Aleksandra , Berchuck, Andrew , Doherty, Jennifer A. , Tyrer, Jonathan P. , Fridley, Brooke L. , Fazio, Anna de , Rudolph, Anja , Lambrechts, Diether , Kjaer, Susanne K , Ramus, Susan J , Hein, Alexander , Jensen, Allan , Vierkant, Robert A , Eccles, Diana , Menon, Usha , Orlow, Irene , Campbell, Ian G , Menkiszak, Janusz , Brown, Robert , Fogarty, Zachary C , Flanagan, James M , Heitz, Florian , Kupryjanczyk, Jolanta , Lambrechts, Diether , Sieh, Weiva , García-Closas, Montserrat , Ekici, Arif B , Chenevix-Trench, Georgia , Høgdall, Estrid , Høgdall, Claus K , Lubinski, Jan , Goodman, Marc T , Bandera, Elisa V.
Cancer Epidemiology, Biomarkers & Prevention | March 19, 2013 | Volume: 22 | Issue: 5 | Pages: 987-992
Abstract Background: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. Methods: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. Results: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. Conclusions: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987–. ©2013 AACR.