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 |
|---|---|
| Pages (from-to) | 1362-1370 |
| Number of pages | 9 |
| Journal | Cancer Epidemiology Biomarkers and Prevention |
| Volume | 21 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - Aug 2012 |
ASJC Scopus subject areas
- Epidemiology
- Oncology
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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; 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 journal › Article › peer-review
}
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.
UR - http://www.scopus.com/inward/record.url?scp=84864821854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864821854&partnerID=8YFLogxK
U2 - 10.1158/1055-9965.EPI-12-0229
DO - 10.1158/1055-9965.EPI-12-0229
M3 - Article
C2 - 22729394
AN - SCOPUS:84864821854
VL - 21
SP - 1362
EP - 1370
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
SN - 1055-9965
IS - 8
ER -