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Neuhausen SL , Brummel S , Ding YC , Singer CF , Pfeiler G , Lynch HT , Nathanson KL , Rebbeck TR , Garber JE , Couch F , Weitzel J , Narod SA , Ganz PA , Daly MB , Godwin AK , Isaacs C , Olopade OI , Tomlinson G , Rubinstein WS , Tung N , Blum JL , Gillen DL
Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers
Breast Cancer Research. 2009 ;11(5)
PMID: ISI:000273342300021    PMCID: PMC2790858   
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Introduction Women who carry mutations in BRCA1 and BRCA2 have a substantially increased risk of developing breast cancer as compared with the general population. However, risk estimates range from 20 to 80%, suggesting the presence of genetic and/or environmental risk modifiers. Based on extensive in vivo and in vitro studies, one important pathway for breast cancer pathogenesis may be the insulin-like growth factor (IGF) signaling pathway, which regulates both cellular proliferation and apoptosis. BRCA1 has been shown to directly interact with IGF signaling such that variants in this pathway may modify risk of cancer in women carrying BRCA mutations. In this study, we investigate the association of variants in genes involved in IGF signaling and risk of breast cancer in women who carry deleterious BRCA1 and BRCA2 mutations. Methods A cohort of 1,665 adult, female mutation carriers, including 1,122 BRCA1 carriers (433 cases) and 543 BRCA2 carriers (238 cases) were genotyped for SNPs in IGF1, IGF1 receptor (IGF1R), IGF1 binding protein (IGFBP1, IGFBP2, IGFBP5), and IGF receptor substrate 1 (IRS1). Cox proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was assumed; and for single SNP analyses, no additivity assumptions were made. Results Among BRCA1 carriers, significant associations were found between risk of breast cancer and LD blocks in IGF1R (global P = 0.011 for LD block 2 and global P = 0.012 for LD block 11). Among BRCA2 carriers, an LD block in IGFBP2 (global P = 0.0145) was found to be associated with the time to breast cancer diagnosis. No significant LD block associations were found for the other investigated genes among BRCA1 and BRCA2 carriers. Conclusions This is the first study to investigate the role of genetic variation in IGF signaling and breast cancer risk in women carrying deleterious mutations in BRCA1 and BRCA2. We identified significant associations in variants in IGF1R and IRS1 in BRCA1 carriers and in IGFBP2 in BRCA2 carriers. Although there is known to be interaction of BRCA1 and IGF signaling, further replication and identification of causal mechanisms are needed to better understand these associations.
Neuhausen, Susan L. Brummel, Sean Ding, Yuan Chun Singer, Christian F. Pfeiler, Georg Lynch, Henry T. Nathanson, Katherine L. Rebbeck, Timothy R. Garber, Judy E. Couch, Fergus Weitzel, Jeffrey Narod, Steven A. Ganz, Patricia A. Daly, Mary B. Godwin, Andrew K. Isaacs, Claudine Olopade, Olufunmilayo I. Tomlinson, Gail Rubinstein, Wendy S. Tung, Nadine Blum, Joanne L. Gillen, Daniel L. Nebraska Department of Health and Human Services ; NIH [5UO1 CA86389, R01-CA083855, R01-CA74415, R01-CA102776, P50CA83638, 5U01CA113916, U01CA69631] The Modifiers and Genetics in Cancer Consortium includes the following centers and individuals: Baylor-Charles A. Sammons Cancer Center (Joanne L Blum, Becky Althaus, Gaby Ethington), Beth Israel Deaconess Medical Center (Nadine Tung), City of Hope National Medical Center (Veronica Lagos, Jeffery Weitzel), Creighton University (Carrie Snyder, Henry T Lynch, Patrice Watson), Dana Farber Cancer Institute (Kathryn Stoeckert, Judy E Garber), Northshore University Health System for Medical Genetics (Suzanne M O'Neill, Christina Selkirk, Wendy S Rubinstein), Fox Chase Cancer Center (Mary B Daly, Andrew K Godwin), Georgetown University (Claudine Isaacs), Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (Joyce Seldon, Patricia A Ganz), Mayo Clinic College of Medicine (Linda Wadum, Fergus Couch), University of Chicago (Shelly Cummings, Olufunmilayo Olopade), University of California, Irvine (Susan L Neuhausen, Linda Steele), University of Pennsylvania Health System (Susan Domchek, Katherine Nathanson Tara Friebel, Timothy Rebbeck), University of Texas, San Antonio (Gail Tomlinson), University of Vienna (Christian Singer), and Women's College Hospital (Steven A Narod). This publication was supported in part by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. The article's contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also received from NIH grants 5UO1 CA86389 (to HTL), R01-CA083855, R01-CA74415 (to SLN), R01-CA102776, R01-CA083855 (to TRR), P50CA83638, 5U01CA113916 (to AKG), and U01CA69631 (to MBD). 53 Biomed central ltd; 236 grays inn rd, floor 6, london wc1x 8hl, england 540od