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A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers

Ding, Yuan C.; McGuffog, Lesley; Healey, Sue; Friedman, Eitan; Laitman, Yael; Paluch-Shimon, Shani; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika and Olsson, Håkan LU , et al. (2012) In Cancer Epidemiology Biomarkers & Prevention 21(8). p.1362-1370
Abstract
Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class... (More)
Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362-70. (C)2012 AACR. (Less)
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Cancer Epidemiology Biomarkers & Prevention
volume
21
issue
8
pages
1362 - 1370
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American Association for Cancer Research
external identifiers
  • wos:000307433800016
  • scopus:84864821854
ISSN
1538-7755
DOI
10.1158/1055-9965.EPI-12-0229
language
English
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yes
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bd943790-9666-435e-aed0-6c31920a495d (old id 3059367)
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2012-10-05 07:13:54
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@article{bd943790-9666-435e-aed0-6c31920a495d,
  abstract     = {Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. Methods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. Results: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). Conclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(8); 1362-70. (C)2012 AACR.},
  author       = {Ding, Yuan C. and McGuffog, Lesley and Healey, Sue and Friedman, Eitan and Laitman, Yael and Paluch-Shimon, Shani and Kaufman, Bella and Liljegren, Annelie and Lindblom, Annika and Olsson, Håkan and Kristoffersson, Ulf and Stenmark-Askmalm, Marie and Melin, Beatrice and Domchek, Susan M. and Nathanson, Katherine L. and Rebbeck, Timothy R. and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Gronwald, Jacek and Huzarski, Tomasz and Cybulski, Cezary and Byrski, Tomasz and Osorio, Ana and Ramony Cajal, Teresa and Stavropoulou, Alexandra V. and Benitez, Javier and Hamann, Ute and Rookus, Matti and Aalfs, Cora M. and de Lange, Judith L. and Meijers-Heijboer, Hanne E. J. and Oosterwijk, Jan C. and van Asperen, Christi J. and Garcia, Encarna B. Gomez and Hoogerbrugge, Nicoline and Jager, Agnes and van der Luijt, Rob B. and Easton, Douglas F. and Peock, Susan and Frost, Debra and Ellis, Steve D. and Platte, Radka and Fineberg, Elena and Evans, D. Gareth and Lalloo, Fiona and Izatt, Louise and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Eccles, Diana and Cole, Trevor and Cook, Jackie and Brewer, Carole and Tischkowitz, Marc and Godwin, Andrew K. and Pathak, Harsh and Stoppa-Lyonnet, Dominique and Sinilnikova, Olga M. and Mazoyer, Sylvie and Barjhoux, Laure and Leone, Melanie and Gauthier-Villars, Marion and Caux-Moncoutier, Virginie and de Pauw, Antoine and Hardouin, Agnes and Berthet, Pascaline and Dreyfus, Helene and Ferrer, Sandra Fert and Collonge-Rame, Marie-Agnes and Sokolowska, Johanna and Buys, Saundra and Daly, Mary and Miron, Alex and Terry, Mary Beth and Chung, Wendy and John, Esther M. and Southey, Melissa and Goldgar, David and Singer, Christian F. and Tea, Muy-Kheng Maria and Gschwantler-Kaulich, Daphne and Fink-Retter, Anneliese and Hansen, Thomas V. O. and Ejlertsen, Bent and Johannsson, Oskar T. and Offit, Kenneth and Sarrel, Kara and Gaudet, Mia M. and Vijai, Joseph and Robson, Mark and Piedmonte, Marion R. and Andrews, Lesley and Cohn, David and DeMars, Leslie R. and DiSilvestro, Paul and Rodriguez, Gustavo and Toland, Amanda Ewart and Montagna, Marco and Agata, Simona and Imyanitov, Evgeny and Isaacs, Claudine and Janavicius, Ramunas and Lazaro, Conxi and Blanco, Ignacio and Ramus, Susan J. and Sucheston, Lara and Karlan, Beth Y. and Gross, Jenny and Ganz, Patricia A. and Beattie, Mary S. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Meindl, Alfons and Arnold, Norbert and Niederacher, Dieter and Preisler-Adams, Sabine and Gadzicki, Dorotehea and Varon-Mateeva, Raymonda and Deissler, Helmut and Gehrig, Andrea and Sutter, Christian and Kast, Karin and Nevanlinna, Heli and Aittomaki, Kristiina and Simard, Jacques and Spurdle, Amanda B. and Beesley, Jonathan and Chen, Xiaoqing and Tomlinson, Gail E. and Weitzel, Jeffrey and Garber, Judy E. and Olopade, Olufunmilayo I. and Rubinstein, Wendy S. and Tung, Nadine and Blum, Joanne L. and Narod, Steven A. and Brummel, Sean and Gillen, Daniel L. and Lindor, Noralane and Fredericksen, Zachary and Pankratz, Vernon S. and Couch, Fergus J. and Radice, Paolo and Peterlongo, Paolo and Greene, Mark H. and Loud, Jennifer T. and Mai, Phuong L. and Andrulis, Irene L. and Glendon, Gord and Ozcelik, Hilmi and Gerdes, Anne-Marie and Thomassen, Mads and Jensen, Uffe Birk and Skytte, Anne-Bine and Caligo, Maria A. and Lee, Andrew and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Neuhausen, Susan L.},
  issn         = {1538-7755},
  language     = {eng},
  number       = {8},
  pages        = {1362--1370},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Epidemiology Biomarkers & Prevention},
  title        = {A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers},
  url          = {http://dx.doi.org/10.1158/1055-9965.EPI-12-0229},
  volume       = {21},
  year         = {2012},
}