The University of Southampton
University of Southampton Institutional Repository

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

A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
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.
1055-9965
1362-1370
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Ding, Yuan C., McGuffog, Lesley, Healey, Sue, Friedman, Eitan, Laitman, Yael, Paluch-Shimon, Shani, 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., Benitez, Javier, Hamann, Ute, Rookus, Matti, Aalfs, Cora M., de Lange, Judith L., Meijers-Heijboer, Hanne E.J., Oosterwijk, Jan C., van Asperen, Christi J., Gomez Garcia, 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, Agnès, Berthet, Pascaline, Dreyfus, Hélène, Ferrer, Sandra Fert, Collonge-Rame, Marie-Agnès, Sokolowska, Johanna, Buys, Sandra, Daly, Mary, Miron, Alex, Terry, M.B., Chung, W., John, E.M., Southey, M., Goldgar, D., Singer, C.F., Tea, M.-K.M., Gschwantler-Kaulich, D., Fink-Retter, A., Hansen, T.V.O., Ejlertsen, B., Johannsson, O.T., Offit, K., Sarrel, K., Gaudet, M.M., Vijai, J., Robson, M., Piedmonte, M.R., Andrews, L., Cohn, D., DeMars, L.R., DiSilvestro, P., Rodriguez, G., Toland, A.E., Montagna, M., Agata, S., Imyanitov, E., Isaacs, C., Janavicius, R., Lazaro, C., Blanco, I., Ramus, S.J., Sucheston, L., Karlan, B.Y., Gross, J., Ganz, P.A., Beattie, M.S., Schmutzler, R.K., 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., Aittomaki, K., Simard, J., Spurdle, A.B., Beesley, J., Chen, X., Tomlinson, G.E., Weitzel, J., Garber, J.E., Olopade, O.I., Rubinstein, W.S., Tung, N., Blum, J.L., Narod, S.A., Brummel, S., Gillen, D.L., Lindor, N., Fredericksen, Z., Pankratz, V.S., Couch, F.J., Radice, P., Peterlongo, P., Greene, M.H., Loud, J.T., Mai, P.L., Andrulis, I.L., Glendon, G., Ozcelik, H., Gerdes, A.-M., Thomassen, M., Jensen, U.B., Skytte, A.-B., Caligo, M.A., Lee, A., Chenevix-Trench, G., Antoniou, A.C. and Neuhausen, S.L. (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 & Prevention, 21 (8), 1362-1370. (doi:10.1158/1055-9965.EPI-12-0229). (PMID:22729394)

Record type: Article

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.

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Published date: August 2012
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 352311
URI: https://eprints.soton.ac.uk/id/eprint/352311
ISSN: 1055-9965
PURE UUID: c05cb6fc-9266-4f0f-990d-9401b7636b2c

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Date deposited: 09 May 2013 10:32
Last modified: 16 Jul 2019 21:34

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Contributors

Author: Yuan C. Ding
Author: Lesley McGuffog
Author: Sue Healey
Author: Eitan Friedman
Author: Yael Laitman
Author: Shani Paluch-Shimon
Author: Bella Kaufman
Author: Annelie Liljegren
Author: Annika Lindblom
Author: Håkan Olsson
Author: Ulf Kristoffersson
Author: Marie Stenmark-Askmalm
Author: Beatrice Melin
Author: Susan M. Domchek
Author: Katherine L. Nathanson
Author: Timothy R. Rebbeck
Author: Anna Jakubowska
Author: Jan Lubinski
Author: Katarzyna Jaworska
Author: Katarzyna Durda
Author: Jacek Gronwald
Author: Tomasz Huzarski
Author: Cezary Cybulski
Author: Tomasz Byrski
Author: Ana Osorio
Author: Teresa Ramóny Cajal
Author: Alexandra V. Stavropoulou
Author: Javier Benitez
Author: Ute Hamann
Author: Matti Rookus
Author: Cora M. Aalfs
Author: Judith L. de Lange
Author: Hanne E.J. Meijers-Heijboer
Author: Jan C. Oosterwijk
Author: Christi J. van Asperen
Author: Encarna B. Gomez Garcia
Author: Nicoline Hoogerbrugge
Author: Agnes Jager
Author: Rob B. van der Luijt
Author: Douglas F. Easton
Author: Susan Peock
Author: Debra Frost
Author: Steve D. Ellis
Author: Radka Platte
Author: Elena Fineberg
Author: D. Gareth Evans
Author: Fiona Lalloo
Author: Louise Izatt
Author: Ros Eeles
Author: Julian Adlard
Author: Rosemarie Davidson
Author: Diana Eccles
Author: Trevor Cole
Author: Jackie Cook
Author: Carole Brewer
Author: Marc Tischkowitz
Author: Andrew K. Godwin
Author: Harsh Pathak
Author: Dominique Stoppa-Lyonnet
Author: Olga M. Sinilnikova
Author: Sylvie Mazoyer
Author: Laure Barjhoux
Author: Mélanie Léoné
Author: Marion Gauthier-Villars
Author: Virginie Caux-Moncoutier
Author: Antoine de Pauw
Author: Agnès Hardouin
Author: Pascaline Berthet
Author: Hélène Dreyfus
Author: Sandra Fert Ferrer
Author: Marie-Agnès Collonge-Rame
Author: Johanna Sokolowska
Author: Sandra Buys
Author: Mary Daly
Author: Alex Miron
Author: M.B. Terry
Author: W. Chung
Author: E.M. John
Author: M. Southey
Author: D. Goldgar
Author: C.F. Singer
Author: M.-K.M. Tea
Author: D. Gschwantler-Kaulich
Author: A. Fink-Retter
Author: T.V.O. Hansen
Author: B. Ejlertsen
Author: O.T. Johannsson
Author: K. Offit
Author: K. Sarrel
Author: M.M. Gaudet
Author: J. Vijai
Author: M. Robson
Author: M.R. Piedmonte
Author: L. Andrews
Author: D. Cohn
Author: L.R. DeMars
Author: P. DiSilvestro
Author: G. Rodriguez
Author: A.E. Toland
Author: M. Montagna
Author: S. Agata
Author: E. Imyanitov
Author: C. Isaacs
Author: R. Janavicius
Author: C. Lazaro
Author: I. Blanco
Author: S.J. Ramus
Author: L. Sucheston
Author: B.Y. Karlan
Author: J. Gross
Author: P.A. Ganz
Author: M.S. Beattie
Author: R.K. Schmutzler
Author: B. Wappenschmidt
Author: A. Meindl
Author: N. Arnold
Author: D. Niederacher
Author: S. Preisler-Adams
Author: D. Gadzicki
Author: R. Varon-Mateeva
Author: H. Deissler
Author: A. Gehrig
Author: C. Sutter
Author: K. Kast
Author: H. Nevanlinna
Author: K. Aittomaki
Author: J. Simard
Author: A.B. Spurdle
Author: J. Beesley
Author: X. Chen
Author: G.E. Tomlinson
Author: J. Weitzel
Author: J.E. Garber
Author: O.I. Olopade
Author: W.S. Rubinstein
Author: N. Tung
Author: J.L. Blum
Author: S.A. Narod
Author: S. Brummel
Author: D.L. Gillen
Author: N. Lindor
Author: Z. Fredericksen
Author: V.S. Pankratz
Author: F.J. Couch
Author: P. Radice
Author: P. Peterlongo
Author: M.H. Greene
Author: J.T. Loud
Author: P.L. Mai
Author: I.L. Andrulis
Author: G. Glendon
Author: H. Ozcelik
Author: A.-M. Gerdes
Author: M. Thomassen
Author: U.B. Jensen
Author: A.-B. Skytte
Author: M.A. Caligo
Author: A. Lee
Author: G. Chenevix-Trench
Author: A.C. Antoniou
Author: S.L. Neuhausen

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