Genetic variation in insulin-like growth factor signaling genes and breast cancer risk among BRCA1 and BRCA2 carriers

被引：41

作者：

Neuhausen, Susan L. ^{[1
]}

Brummel, Sean ^{[2
]}

Ding, Yuan Chun ^{[1
]}

Singer, Christian F. ^{[3
]}

Pfeiler, Georg ^{[3
]}

Lynch, Henry T. ^{[4
]}

Nathanson, Katherine L. ^{[5
]}

Rebbeck, Timothy R. ^{[6
]}

Garber, Judy E. ^{[7
]}

Couch, Fergus ^{[8
]}

Weitzel, Jeffrey ^{[9
]}

Narod, Steven A. ^{[10
]}

Ganz, Patricia A. ^{[11
,12
]}

Daly, Mary B. ^{[13
]}

Godwin, Andrew K. ^{[14
]}

Isaacs, Claudine ^{[15
]}

Olopade, Olufunmilayo I. ^{[16
,17
]}

Tomlinson, Gail ^{[18
]}

Rubinstein, Wendy S. ^{[19
]}

Tung, Nadine ^{[20
]}

Blum, Joanne L. ^{[21
]}

Gillen, Daniel L. ^{[1
,2
]}

机构：

[1] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Dept Stat, Irvine, CA 92697 USA

[3] Med Univ Vienna, Div Special Gynecol, Dept Obstet & Gynaecol, A-1090 Vienna, Austria

[4] Creighton Univ, Dept Prevent Med & Publ Hlth, Sch Med, Omaha, NE 68182 USA

[5] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA

[6] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[7] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA

[8] Mayo Clin, Mayo Dept Lab Med & Pathol, Rochester, MN 55905 USA

[9] City Hope Natl Med Ctr, Dept Populat Sci, Div Clin Canc Genet, Duarte, CA 91010 USA

[10] Womens Coll Hosp, Womens Coll, Res Inst, Toronto, ON M5G 1N8, Canada

[11] UCLA Sch Med, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA

[12] UCLA Sch Publ Hlth, Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA 90095 USA

[13] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA

[14] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA

[15] Georgetown Univ, Dept Med & Oncol, Washington, DC 20007 USA

[16] Univ Chicago, Dept Med, Chicago, IL 60637 USA

[17] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[18] Univ Texas Hlth Sci Ctr San Antonio, Div Pediat Hematol Oncol, San Antonio, TX 78229 USA

[19] NorthShore Univ Hlth Syst, Dept Med, Evanston, IL 60201 USA

[20] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA

[21] Baylor Univ, Dept Oncol, Med Ctr, Dallas, TX 75246 USA

来源：

BREAST CANCER RESEARCH | 2009年 / 11卷 / 05期

关键词：

SINGLE-NUCLEOTIDE POLYMORPHISM; BINDING PROTEIN-5 IGFBP-5; MUTATION CARRIERS; FACTOR-I; MULTIETHNIC COHORT; OVARIAN-CANCER; MAMMOGRAPHIC DENSITY; THERAPEUTIC TARGET; CIRCULATING LEVELS; COMMON VARIANTS;

D O I：

10.1186/bcr2414

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：12

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