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; 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; Anne-Marie Gerdes; SWE-BRCA

doi:10.1158/1055-9965.EPI-12-0229

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 DurdaJacek 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, Anne-Marie Gerdes, SWE-BRCA

17 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 language	English
Journal	Cancer Epidemiology, Biomarkers & Prevention
Volume	21
Issue number	8
Pages (from-to)	1362-70
Number of pages	9
ISSN	1055-9965
DOIs	https://doi.org/10.1158/1055-9965.EPI-12-0229
Publication status	Published - Aug 2012

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Ding, Y. C., McGuffog, L., Healey, S., Friedman, E., Laitman, Y., Paluch-Shimon, S., Kaufman, B., Liljegren, A., Lindblom, A., Olsson, H., Kristoffersson, U., Stenmark-Askmalm, M., Melin, B., Domchek, S. M., Nathanson, K. L., Rebbeck, T. R., Jakubowska, A., Lubinski, J., Jaworska, K., ... SWE-BRCA (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), 1362-70. https://doi.org/10.1158/1055-9965.EPI-12-0229

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 et al.

In: Cancer Epidemiology, Biomarkers & Prevention, Vol. 21, No. 8, 08.2012, p. 1362-70.

Research output: Contribution to journal › Journal article › Research › peer-review

Ding, YC, McGuffog, L, Healey, S, Friedman, E, Laitman, Y, Paluch-Shimon, S, 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, Gerdes, A-M & SWE-BRCA 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, vol. 21, no. 8, pp. 1362-70. https://doi.org/10.1158/1055-9965.EPI-12-0229

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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 Shani- Paluch-Shimon 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 Anne-Marie Gerdes and Gerdes, {Anne-Marie Ax{\o}}",

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doi = "10.1158/1055-9965.EPI-12-0229",

language = "English",

volume = "21",

pages = "1362--70",

journal = "Cancer Epidemiology, Biomarkers & Prevention",

issn = "1055-9965",

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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 - Paluch-Shimon, Shani-

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 - Gerdes, Anne-Marie

AU - SWE-BRCA

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.

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

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

M3 - Journal article

C2 - 22729394

SN - 1055-9965

VL - 21

SP - 1362

EP - 1370

JO - Cancer Epidemiology, Biomarkers & Prevention

JF - Cancer Epidemiology, Biomarkers & Prevention

IS - 8

ER -

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

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