A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

Yuan C. Ding, Lesley McGuffog, Sue Healey, Eitan Friedman, Yael Laitman, Shani Paluch Shimon, Bella Kaufman, Annelie Liljegren, Annika Lindblom, Håkan Olsson, Ulf Kristoffersson, Marie Stenmark-Askmalm, Beatrice Melin, Susan M. Domchek, Katherine L. Nathanson, Timothy R. Rebbeck, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska, Katarzyna Durda & 141 others Jacek Gronwald, Tomasz Huzarski, Cezary Cybulski, Tomasz Byrski, Ana Osorio, Teresa Ramóny Cajal, Alexandra V. Stavropoulou, Javier Benítez, Ute Hamann, Matti Rookus, Cora M. Aalfs, Judith L. De Lange, Hanne E J Meijers-Heijboer, Jan C. Oosterwijk, Christi J. Van Asperen, Encarna B. Gómez García, Nicoline Hoogerbrugge, Agnes Jager, Rob B. Van Der Luijt, Douglas F. Easton, Susan Peock, Debra Frost, Steve D. Ellis, Radka Platte, Elena Fineberg, D. Gareth Evans, Fiona Lalloo, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Diana Eccles, Trevor Cole, Jackie Cook, Carole Brewer, Marc Tischkowitz, Andrew K. Godwin, Harsh Pathak, Dominique Stoppa-Lyonnet, Olga M. Sinilnikova, Sylvie Mazoyer, Laure Barjhoux, Mélanie Léoné, Marion Gauthier-Villars, Virginie Caux-Moncoutier, Antoine De Pauw, Agnés Hardouin, Pascaline Berthet, Héléne Dreyfus, Sandra Fert Ferrer, Marie Agnés Collonge-Rame, Johanna Sokolowska, Saundra Buys, Mary Daly, Alex Miron, Mary Beth Terry, Wendy Chung, Esther M. John, Melissa Southey, David Goldgar, Christian F. Singer, Muy Kheng Maria Tea, Daphne Gschwantler-Kaulich, Anneliese Fink-Retter, Thomas V O Hansen, Bent Ejlertsen, Oskar T. Johannsson, Kenneth Offi, Kara Sarrel, Mia M. Gaudet, Joseph Vijai, Mark Robson, Marion R. Piedmonte, Lesley Andrews, David Cohn, Leslie R. DeMars, Paul DiSilvestro, Gustavo Rodriguez, Amanda Ewart Toland, Marco Montagna, Simona Agata, Evgeny Imyanitov, Claudine Isaacs, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Susan J. Ramus, Lara Sucheston, Beth Y. Karlan, Jenny Gross, Patricia A. Ganz, Mary S. Beattie, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Sabine Preisler-Adams, Dorotehea Gadzicki, Raymonda Varon-Mateeva, Helmut Deissler, Andrea Gehrig, Christian Sutter, Karin Kast, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Gail E. Tomlinson, Jeffrey Weitzel, Judy E. Garber, Olufunmilayo I. Olopade, Wendy S. Rubinstein, Nadine Tung, Joanne L. Blum, Steven A. Narod, Sean Brummel, Daniel L. Gillen, Noralane Lindor, Zachary Fredericksen, Vernon S. Pankratz, Fergus J. Couch, Paolo Radice, Paolo Peterlongo, Mark H. Greene, Jennifer T. Loud, Phuong L. Mai, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Anne Marie Gerdes, Mads Thomassen, Uffe Birk Jensen, Anne Bine Skytte, Maria A. Caligo, Andrew Lee, Georgia Chenevix-Trench, Antonis C. Antoniou, Susan L. Neuhausen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen 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; Pdifference, 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.

Original languageEnglish
Pages (from-to)1362-1370
Number of pages9
JournalCancer Epidemiology Biomarkers and Prevention
Volume21
Issue number8
DOIs
Publication statusPublished - Aug 2012

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Insulin Receptor Substrate Proteins
Ovarian Neoplasms
Breast Neoplasms
Mutation
Confidence Intervals
Somatomedins
Single Nucleotide Polymorphism
Research Personnel

ASJC Scopus subject areas

  • Epidemiology
  • Oncology

Cite this

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; Shimon, Shani Paluch; Kaufman, Bella; Liljegren, Annelie; Lindblom, Annika; Olsson, Håkan; Kristoffersson, Ulf; Stenmark-Askmalm, Marie; Melin, Beatrice; Domchek, Susan M.; Nathanson, Katherine L.; Rebbeck, Timothy R.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Gronwald, Jacek; Huzarski, Tomasz; Cybulski, Cezary; Byrski, Tomasz; Osorio, Ana; Cajal, Teresa Ramóny; Stavropoulou, Alexandra V.; Benítez, Javier; Hamann, Ute; Rookus, Matti; Aalfs, Cora M.; De Lange, Judith L.; Meijers-Heijboer, Hanne E J; Oosterwijk, Jan C.; Van Asperen, Christi J.; Gómez García, Encarna B.; Hoogerbrugge, Nicoline; Jager, Agnes; Van Der Luijt, Rob B.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Ellis, Steve D.; Platte, Radka; Fineberg, Elena; Evans, D. Gareth; Lalloo, Fiona; Izatt, Louise; Eeles, Ros; Adlard, Julian; Davidson, Rosemarie; Eccles, Diana; Cole, Trevor; Cook, Jackie; Brewer, Carole; Tischkowitz, Marc; Godwin, Andrew K.; Pathak, Harsh; Stoppa-Lyonnet, Dominique; Sinilnikova, Olga M.; Mazoyer, Sylvie; Barjhoux, Laure; Léoné, Mélanie; Gauthier-Villars, Marion; Caux-Moncoutier, Virginie; De Pauw, Antoine; Hardouin, Agnés; Berthet, Pascaline; Dreyfus, Héléne; Ferrer, Sandra Fert; Collonge-Rame, Marie Agnés; Sokolowska, Johanna; Buys, Saundra; Daly, Mary; Miron, Alex; Terry, Mary Beth; Chung, Wendy; John, Esther M.; Southey, Melissa; Goldgar, David; Singer, Christian F.; Tea, Muy Kheng Maria; Gschwantler-Kaulich, Daphne; Fink-Retter, Anneliese; Hansen, Thomas V O; Ejlertsen, Bent; Johannsson, Oskar T.; Offi, Kenneth; Sarrel, Kara; Gaudet, Mia M.; Vijai, Joseph; Robson, Mark; Piedmonte, Marion R.; Andrews, Lesley; Cohn, David; DeMars, Leslie R.; DiSilvestro, Paul; Rodriguez, Gustavo; Toland, Amanda Ewart; Montagna, Marco; Agata, Simona; Imyanitov, Evgeny; Isaacs, Claudine; Janavicius, Ramunas; Lazaro, Conxi; Blanco, Ignacio; Ramus, Susan J.; Sucheston, Lara; Karlan, Beth Y.; Gross, Jenny; Ganz, Patricia A.; Beattie, Mary S.; Schmutzler, Rita K.; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Niederacher, Dieter; Preisler-Adams, Sabine; Gadzicki, Dorotehea; Varon-Mateeva, Raymonda; Deissler, Helmut; Gehrig, Andrea; Sutter, Christian; Kast, Karin; Nevanlinna, Heli; Aittomäki, Kristiina; Simard, Jacques; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Tomlinson, Gail E.; Weitzel, Jeffrey; Garber, Judy E.; Olopade, Olufunmilayo I.; Rubinstein, Wendy S.; Tung, Nadine; Blum, Joanne L.; Narod, Steven A.; Brummel, Sean; Gillen, Daniel L.; Lindor, Noralane; Fredericksen, Zachary; Pankratz, Vernon S.; Couch, Fergus J.; Radice, Paolo; Peterlongo, Paolo; Greene, Mark H.; Loud, Jennifer T.; Mai, Phuong L.; Andrulis, Irene L.; Glendon, Gord; Ozcelik, Hilmi; Gerdes, Anne Marie; Thomassen, Mads; Jensen, Uffe Birk; Skytte, Anne Bine; Caligo, Maria A.; Lee, Andrew; Chenevix-Trench, Georgia; Antoniou, Antonis C.; Neuhausen, Susan L.

In: Cancer Epidemiology Biomarkers and Prevention, Vol. 21, No. 8, 08.2012, p. 1362-1370.

Research output: Contribution to journalArticle

Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Shimon, SP, Kaufman, B, Liljegren, A, Lindblom, A, Olsson, H, Kristoffersson, U, Stenmark-Askmalm, M, Melin, B, Domchek, SM, Nathanson, KL, Rebbeck, TR, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Gronwald, J, Huzarski, T, Cybulski, C, Byrski, T, Osorio, A, Cajal, TR, Stavropoulou, AV, Benítez, J, Hamann, U, Rookus, M, Aalfs, CM, De Lange, JL, Meijers-Heijboer, HEJ, Oosterwijk, JC, Van Asperen, CJ, Gómez García, EB, Hoogerbrugge, N, Jager, A, Van Der Luijt, RB, Easton, DF, Peock, S, Frost, D, Ellis, SD, Platte, R, Fineberg, E, Evans, DG, Lalloo, F, Izatt, L, Eeles, R, Adlard, J, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Tischkowitz, M, Godwin, AK, Pathak, H, Stoppa-Lyonnet, D, Sinilnikova, OM, Mazoyer, S, Barjhoux, L, Léoné, M, Gauthier-Villars, M, Caux-Moncoutier, V, De Pauw, A, Hardouin, A, Berthet, P, Dreyfus, H, Ferrer, SF, Collonge-Rame, MA, Sokolowska, J, Buys, S, Daly, M, Miron, A, Terry, MB, Chung, W, John, EM, Southey, M, Goldgar, D, Singer, CF, Tea, MKM, Gschwantler-Kaulich, D, Fink-Retter, A, Hansen, TVO, Ejlertsen, B, Johannsson, OT, Offi, K, Sarrel, K, Gaudet, MM, Vijai, J, Robson, M, Piedmonte, MR, Andrews, L, Cohn, D, DeMars, LR, DiSilvestro, P, Rodriguez, G, Toland, AE, Montagna, M, Agata, S, Imyanitov, E, Isaacs, C, Janavicius, R, Lazaro, C, Blanco, I, Ramus, SJ, Sucheston, L, Karlan, BY, Gross, J, Ganz, PA, Beattie, MS, Schmutzler, RK, Wappenschmidt, B, Meindl, A, Arnold, N, Niederacher, D, Preisler-Adams, S, Gadzicki, D, Varon-Mateeva, R, Deissler, H, Gehrig, A, Sutter, C, Kast, K, Nevanlinna, H, Aittomäki, K, Simard, J, Spurdle, AB, Beesley, J, Chen, X, Tomlinson, GE, Weitzel, J, Garber, JE, Olopade, OI, Rubinstein, WS, Tung, N, Blum, JL, Narod, SA, Brummel, S, Gillen, DL, Lindor, N, Fredericksen, Z, Pankratz, VS, Couch, FJ, Radice, P, Peterlongo, P, Greene, MH, Loud, JT, Mai, PL, Andrulis, IL, Glendon, G, Ozcelik, H, Gerdes, AM, Thomassen, M, Jensen, UB, Skytte, AB, Caligo, MA, Lee, A, Chenevix-Trench, G, Antoniou, AC & Neuhausen, SL 2012, 'A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers', Cancer Epidemiology Biomarkers and Prevention, vol. 21, no. 8, pp. 1362-1370. https://doi.org/10.1158/1055-9965.EPI-12-0229
Ding, Yuan C. ; McGuffog, Lesley ; Healey, Sue ; Friedman, Eitan ; Laitman, Yael ; Shimon, Shani Paluch ; Kaufman, Bella ; Liljegren, Annelie ; Lindblom, Annika ; Olsson, Håkan ; Kristoffersson, Ulf ; Stenmark-Askmalm, Marie ; Melin, Beatrice ; Domchek, Susan M. ; Nathanson, Katherine L. ; Rebbeck, Timothy R. ; Jakubowska, Anna ; Lubinski, Jan ; Jaworska, Katarzyna ; Durda, Katarzyna ; Gronwald, Jacek ; Huzarski, Tomasz ; Cybulski, Cezary ; Byrski, Tomasz ; Osorio, Ana ; Cajal, Teresa Ramóny ; Stavropoulou, Alexandra V. ; Benítez, Javier ; Hamann, Ute ; Rookus, Matti ; Aalfs, Cora M. ; De Lange, Judith L. ; Meijers-Heijboer, Hanne E J ; Oosterwijk, Jan C. ; Van Asperen, Christi J. ; Gómez García, Encarna B. ; Hoogerbrugge, Nicoline ; Jager, Agnes ; Van Der Luijt, Rob B. ; Easton, Douglas F. ; Peock, Susan ; Frost, Debra ; Ellis, Steve D. ; Platte, Radka ; Fineberg, Elena ; Evans, D. Gareth ; Lalloo, Fiona ; Izatt, Louise ; Eeles, Ros ; Adlard, Julian ; Davidson, Rosemarie ; Eccles, Diana ; Cole, Trevor ; Cook, Jackie ; Brewer, Carole ; Tischkowitz, Marc ; Godwin, Andrew K. ; Pathak, Harsh ; Stoppa-Lyonnet, Dominique ; Sinilnikova, Olga M. ; Mazoyer, Sylvie ; Barjhoux, Laure ; Léoné, Mélanie ; Gauthier-Villars, Marion ; Caux-Moncoutier, Virginie ; De Pauw, Antoine ; Hardouin, Agnés ; Berthet, Pascaline ; Dreyfus, Héléne ; Ferrer, Sandra Fert ; Collonge-Rame, Marie Agnés ; Sokolowska, Johanna ; Buys, Saundra ; Daly, Mary ; Miron, Alex ; Terry, Mary Beth ; Chung, Wendy ; John, Esther M. ; Southey, Melissa ; Goldgar, David ; Singer, Christian F. ; Tea, Muy Kheng Maria ; Gschwantler-Kaulich, Daphne ; Fink-Retter, Anneliese ; Hansen, Thomas V O ; Ejlertsen, Bent ; Johannsson, Oskar T. ; Offi, Kenneth ; Sarrel, Kara ; Gaudet, Mia M. ; Vijai, Joseph ; Robson, Mark ; Piedmonte, Marion R. ; Andrews, Lesley ; Cohn, David ; DeMars, Leslie R. ; DiSilvestro, Paul ; Rodriguez, Gustavo ; Toland, Amanda Ewart ; Montagna, Marco ; Agata, Simona ; Imyanitov, Evgeny ; Isaacs, Claudine ; Janavicius, Ramunas ; Lazaro, Conxi ; Blanco, Ignacio ; Ramus, Susan J. ; Sucheston, Lara ; Karlan, Beth Y. ; Gross, Jenny ; Ganz, Patricia A. ; Beattie, Mary S. ; Schmutzler, Rita K. ; Wappenschmidt, Barbara ; Meindl, Alfons ; Arnold, Norbert ; Niederacher, Dieter ; Preisler-Adams, Sabine ; Gadzicki, Dorotehea ; Varon-Mateeva, Raymonda ; Deissler, Helmut ; Gehrig, Andrea ; Sutter, Christian ; Kast, Karin ; Nevanlinna, Heli ; Aittomäki, Kristiina ; Simard, Jacques ; Spurdle, Amanda B. ; Beesley, Jonathan ; Chen, Xiaoqing ; Tomlinson, Gail E. ; Weitzel, Jeffrey ; Garber, Judy E. ; Olopade, Olufunmilayo I. ; Rubinstein, Wendy S. ; Tung, Nadine ; Blum, Joanne L. ; Narod, Steven A. ; Brummel, Sean ; Gillen, Daniel L. ; Lindor, Noralane ; Fredericksen, Zachary ; Pankratz, Vernon S. ; Couch, Fergus J. ; Radice, Paolo ; Peterlongo, Paolo ; Greene, Mark H. ; Loud, Jennifer T. ; Mai, Phuong L. ; Andrulis, Irene L. ; Glendon, Gord ; Ozcelik, Hilmi ; Gerdes, Anne Marie ; Thomassen, Mads ; Jensen, Uffe Birk ; Skytte, Anne Bine ; Caligo, Maria A. ; Lee, Andrew ; Chenevix-Trench, Georgia ; Antoniou, Antonis C. ; Neuhausen, Susan L. / A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers. In: Cancer Epidemiology Biomarkers and Prevention. 2012 ; Vol. 21, No. 8. pp. 1362-1370.
@article{24ea2a64a77e43e0b933013a3ec3f230,
title = "A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers",
abstract = "Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen 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; Pdifference, 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.",
author = "Ding, {Yuan C.} and Lesley McGuffog and Sue Healey and Eitan Friedman and Yael Laitman and Shimon, {Shani Paluch} and Bella Kaufman and Annelie Liljegren and Annika Lindblom and H{\aa}kan Olsson and Ulf Kristoffersson and Marie Stenmark-Askmalm and Beatrice Melin and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Rebbeck, {Timothy R.} and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska and Katarzyna Durda and Jacek Gronwald and Tomasz Huzarski and Cezary Cybulski and Tomasz Byrski and Ana Osorio and Cajal, {Teresa Ram{\'o}ny} and Stavropoulou, {Alexandra V.} and Javier Ben{\'i}tez and Ute Hamann and Matti Rookus 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 {G{\'o}mez Garc{\'i}a}, {Encarna B.} and Nicoline Hoogerbrugge and Agnes Jager and {Van Der Luijt}, {Rob B.} and Easton, {Douglas F.} and Susan Peock and Debra Frost and Ellis, {Steve D.} and Radka Platte and Elena Fineberg and Evans, {D. Gareth} and Fiona Lalloo and Louise Izatt and Ros Eeles and Julian Adlard and Rosemarie Davidson and Diana Eccles and Trevor Cole and Jackie Cook and Carole Brewer and Marc Tischkowitz and Godwin, {Andrew K.} and Harsh Pathak and Dominique Stoppa-Lyonnet and Sinilnikova, {Olga M.} and Sylvie Mazoyer and Laure Barjhoux and M{\'e}lanie L{\'e}on{\'e} and Marion Gauthier-Villars and Virginie Caux-Moncoutier and {De Pauw}, Antoine and Agn{\'e}s Hardouin and Pascaline Berthet and H{\'e}l{\'e}ne Dreyfus and Ferrer, {Sandra Fert} and Collonge-Rame, {Marie Agn{\'e}s} and Johanna Sokolowska and Saundra Buys and Mary Daly and Alex Miron and Terry, {Mary Beth} and Wendy Chung and John, {Esther M.} and Melissa Southey and David Goldgar and Singer, {Christian F.} and Tea, {Muy Kheng Maria} and Daphne Gschwantler-Kaulich and Anneliese Fink-Retter and Hansen, {Thomas V O} and Bent Ejlertsen and Johannsson, {Oskar T.} and Kenneth Offi and Kara Sarrel and Gaudet, {Mia M.} and Joseph Vijai and Mark Robson and Piedmonte, {Marion R.} and Lesley Andrews and David Cohn and DeMars, {Leslie R.} and Paul DiSilvestro and Gustavo Rodriguez and Toland, {Amanda Ewart} and Marco Montagna and Simona Agata and Evgeny Imyanitov and Claudine Isaacs and Ramunas Janavicius and Conxi Lazaro and Ignacio Blanco and Ramus, {Susan J.} and Lara Sucheston and Karlan, {Beth Y.} and Jenny Gross and Ganz, {Patricia A.} and Beattie, {Mary S.} and Schmutzler, {Rita K.} and Barbara Wappenschmidt and Alfons Meindl and Norbert Arnold and Dieter Niederacher and Sabine Preisler-Adams and Dorotehea Gadzicki and Raymonda Varon-Mateeva and Helmut Deissler and Andrea Gehrig and Christian Sutter and Karin Kast and Heli Nevanlinna and Kristiina Aittom{\"a}ki and Jacques Simard and Spurdle, {Amanda B.} and Jonathan Beesley and Xiaoqing Chen and Tomlinson, {Gail E.} and Jeffrey Weitzel and Garber, {Judy E.} and Olopade, {Olufunmilayo I.} and Rubinstein, {Wendy S.} and Nadine Tung and Blum, {Joanne L.} and Narod, {Steven A.} and Sean Brummel and Gillen, {Daniel L.} and Noralane Lindor and Zachary Fredericksen and Pankratz, {Vernon S.} and Couch, {Fergus J.} and Paolo Radice and Paolo Peterlongo and Greene, {Mark H.} and Loud, {Jennifer T.} and Mai, {Phuong L.} and Andrulis, {Irene L.} and Gord Glendon and Hilmi Ozcelik and Gerdes, {Anne Marie} and Mads Thomassen and Jensen, {Uffe Birk} and Skytte, {Anne Bine} and Caligo, {Maria A.} and Andrew Lee and Georgia Chenevix-Trench and Antoniou, {Antonis C.} and Neuhausen, {Susan L.}",
year = "2012",
month = "8",
doi = "10.1158/1055-9965.EPI-12-0229",
language = "English",
volume = "21",
pages = "1362--1370",
journal = "Cancer Epidemiology Biomarkers and Prevention",
issn = "1055-9965",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers

AU - Ding, Yuan C.

AU - McGuffog, Lesley

AU - Healey, Sue

AU - Friedman, Eitan

AU - Laitman, Yael

AU - Shimon, Shani Paluch

AU - Kaufman, Bella

AU - Liljegren, Annelie

AU - Lindblom, Annika

AU - Olsson, Håkan

AU - Kristoffersson, Ulf

AU - Stenmark-Askmalm, Marie

AU - Melin, Beatrice

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Rebbeck, Timothy R.

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska, Katarzyna

AU - Durda, Katarzyna

AU - Gronwald, Jacek

AU - Huzarski, Tomasz

AU - Cybulski, Cezary

AU - Byrski, Tomasz

AU - Osorio, Ana

AU - Cajal, Teresa Ramóny

AU - Stavropoulou, Alexandra V.

AU - Benítez, Javier

AU - Hamann, Ute

AU - Rookus, Matti

AU - Aalfs, Cora M.

AU - De Lange, Judith L.

AU - Meijers-Heijboer, Hanne E J

AU - Oosterwijk, Jan C.

AU - Van Asperen, Christi J.

AU - Gómez García, Encarna B.

AU - Hoogerbrugge, Nicoline

AU - Jager, Agnes

AU - Van Der Luijt, Rob B.

AU - Easton, Douglas F.

AU - Peock, Susan

AU - Frost, Debra

AU - Ellis, Steve D.

AU - Platte, Radka

AU - Fineberg, Elena

AU - Evans, D. Gareth

AU - Lalloo, Fiona

AU - Izatt, Louise

AU - Eeles, Ros

AU - Adlard, Julian

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Cole, Trevor

AU - Cook, Jackie

AU - Brewer, Carole

AU - Tischkowitz, Marc

AU - Godwin, Andrew K.

AU - Pathak, Harsh

AU - Stoppa-Lyonnet, Dominique

AU - Sinilnikova, Olga M.

AU - Mazoyer, Sylvie

AU - Barjhoux, Laure

AU - Léoné, Mélanie

AU - Gauthier-Villars, Marion

AU - Caux-Moncoutier, Virginie

AU - De Pauw, Antoine

AU - Hardouin, Agnés

AU - Berthet, Pascaline

AU - Dreyfus, Héléne

AU - Ferrer, Sandra Fert

AU - Collonge-Rame, Marie Agnés

AU - Sokolowska, Johanna

AU - Buys, Saundra

AU - Daly, Mary

AU - Miron, Alex

AU - Terry, Mary Beth

AU - Chung, Wendy

AU - John, Esther M.

AU - Southey, Melissa

AU - Goldgar, David

AU - Singer, Christian F.

AU - Tea, Muy Kheng Maria

AU - Gschwantler-Kaulich, Daphne

AU - Fink-Retter, Anneliese

AU - Hansen, Thomas V O

AU - Ejlertsen, Bent

AU - Johannsson, Oskar T.

AU - Offi, Kenneth

AU - Sarrel, Kara

AU - Gaudet, Mia M.

AU - Vijai, Joseph

AU - Robson, Mark

AU - Piedmonte, Marion R.

AU - Andrews, Lesley

AU - Cohn, David

AU - DeMars, Leslie R.

AU - DiSilvestro, Paul

AU - Rodriguez, Gustavo

AU - Toland, Amanda Ewart

AU - Montagna, Marco

AU - Agata, Simona

AU - Imyanitov, Evgeny

AU - Isaacs, Claudine

AU - Janavicius, Ramunas

AU - Lazaro, Conxi

AU - Blanco, Ignacio

AU - Ramus, Susan J.

AU - Sucheston, Lara

AU - Karlan, Beth Y.

AU - Gross, Jenny

AU - Ganz, Patricia A.

AU - Beattie, Mary S.

AU - Schmutzler, Rita K.

AU - Wappenschmidt, Barbara

AU - Meindl, Alfons

AU - Arnold, Norbert

AU - Niederacher, Dieter

AU - Preisler-Adams, Sabine

AU - Gadzicki, Dorotehea

AU - Varon-Mateeva, Raymonda

AU - Deissler, Helmut

AU - Gehrig, Andrea

AU - Sutter, Christian

AU - Kast, Karin

AU - Nevanlinna, Heli

AU - Aittomäki, Kristiina

AU - Simard, Jacques

AU - Spurdle, Amanda B.

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Tomlinson, Gail E.

AU - Weitzel, Jeffrey

AU - Garber, Judy E.

AU - Olopade, Olufunmilayo I.

AU - Rubinstein, Wendy S.

AU - Tung, Nadine

AU - Blum, Joanne L.

AU - Narod, Steven A.

AU - Brummel, Sean

AU - Gillen, Daniel L.

AU - Lindor, Noralane

AU - Fredericksen, Zachary

AU - Pankratz, Vernon S.

AU - Couch, Fergus J.

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Greene, Mark H.

AU - Loud, Jennifer T.

AU - Mai, Phuong L.

AU - Andrulis, Irene L.

AU - Glendon, Gord

AU - Ozcelik, Hilmi

AU - Gerdes, Anne Marie

AU - Thomassen, Mads

AU - Jensen, Uffe Birk

AU - Skytte, Anne Bine

AU - Caligo, Maria A.

AU - Lee, Andrew

AU - Chenevix-Trench, Georgia

AU - Antoniou, Antonis C.

AU - Neuhausen, Susan L.

PY - 2012/8

Y1 - 2012/8

N2 - Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen 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; Pdifference, 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.

AB - Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk inwomen 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; Pdifference, 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.

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U2 - 10.1158/1055-9965.EPI-12-0229

DO - 10.1158/1055-9965.EPI-12-0229

M3 - Article

VL - 21

SP - 1362

EP - 1370

JO - Cancer Epidemiology Biomarkers and Prevention

JF - Cancer Epidemiology Biomarkers and Prevention

SN - 1055-9965

IS - 8

ER -