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

Susan L Neuhausen1 email, Sean Brummel2 email, Yuan Chun Ding1 email, Christian F Singer3 email, Georg Pfeiler3 email, Henry T Lynch4 email, Katherine L Nathanson5 email, Timothy R Rebbeck6 email, Judy E Garber7 email, Fergus Couch8 email, Jeffrey Weitzel9 email, Steven A Narod10 email, Patricia A Ganz11 email, Mary B Daly12 email, Andrew K Godwin13 email, Claudine Isaacs14 email, Olufunmilayo I Olopade15 email, Gail Tomlinson16 email, Wendy S Rubinstein17 email, Nadine Tung18 email, Joanne L Blum19 email and Daniel L Gillen1,2 email

1  Department of Epidemiology, University of California Irvine, 224 Irvine Hall, Irvine, CA 92697, USA

2  Department of Statistics, University of California Irvine, 2226 Bren Hall, Irvine, CA 92697 USA

3  Division of Special Gynecology, Department of Obstetrics and Gynaecology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria

4  Department of Preventive Medicine and Public Health, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68182, USA

5  Department of Medicine, Medical Genetics, University of Pennsylvania School of Medicine, 351 BRB 2/3, 421 Curie Blvd, Philadelphia, PA 19104, USA

6  Department of Biostatistics and Epidemiology Abramson Cancer Center University of Pennsylvania School of Medicine, 217 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA

7  Department of Adult Oncology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA

8  Mayo Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

9  Division of Clinical Cancer Genetics, Department of Population Sciences, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA

10  Women's College Research Institute, Women's College Hospital, 790 Bay Street, 7th Floor, Toronto, ON M5G 1N8, Canada

11  UCLA Schools of Medicine and Public Health Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 CHS, Los Angeles, CA 90095-6900, USA

12  Department of Clinical Genetics, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

13  Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

14  Department of Medicine and Oncology, Georgetown University, 3800 Reservoir Road, NW, Washington, DC 20007, USA

15  Departments of Medicine and Human Genetics, University of Chicago, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA

16  Division of Pediatric Hematology Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3901, USA

17  Department of Medicine, NorthShore University Health System, 1000 Central Street, Suite 620, Evanston, IL 60201, USA

18  Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA

19  Department of Oncology, Baylor University Medical Center, 3535 Worth St. Suite 600, Dallas, TX 75246, USA

author email corresponding author email

Breast Cancer Research 2009, 11:R76doi:10.1186/bcr2414

Published: 20 October 2009

Abstract

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.

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