Genetic variation in IGFBP2 and IGFBP5 is associated with breast cancer in populations of African descent
- 154 Downloads
The insulin-like growth factor (IGF) signaling pathway is thought to play a major role in the etiology of breast cancer. Although incidence rates of breast cancer overall are lower in African Americans than in Caucasians, African-American women have a higher incidence under age 40 years, are diagnosed with more advanced disease, and have poorer prognosis. We investigated the association of breast cancer and genetic variants in genes in the IGF signaling pathway in a population-based case–control study of African-American women. We found significant associations at a locus encompassing parts of the IGFBP2 and IGFBP5 genes on chromosome 2q35, which we then replicated in a case–control study of Nigerian women. Based on those initial findings, we genotyped a total of 34 single nucleotide polymorphisms (SNPs) across the region in both study populations. Statistically significant associations with breast cancer were observed across approximately 50 kb of DNA sequence encompassing three exons in the 3′ end of IGFBP2 and three exons in the 3′ end of IGFBP5. SNPs were associated with breast cancer risk with P values as low as P = 0.0038 and P = 0.01 in African-Americans and Nigerians, respectively. This study is the first to report associations between genetic variants in IGFBP2 and IGFBP5 and breast cancer risk.
We thank Jocelyn Koo for data management and Karen Kelly and Megan Rounds for genotyping, and Kavita Renduchintala, Ming Li, and Aileen Sy for help with the genotyping. We thank the women who participated in this research. This work was supported by the California Breast Cancer Program 9PB-0142 (to SLN). The multi-ethnic case-control study was supported by grant CA77305 from the National Cancer Institute (NCI) and grant 17-96-1-6071 by the U.S. Department of Defense (to EMJ). The Northern California Family Registry for Breast Cancer was supported by the NCI under RFA#CA95-003 through a cooperative agreement with the Northern California Cancer Center (to EMJ). Collection of the Nigerian case-control population was funded by NCI CA-RO1 89085-01A and the Ralph and Marion Falk Medical Research Trust (to OIO).
- Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P, Pharoah PD, Wareham NJ, Easton DF, Ponder BA, Dunning AM (2006) IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet 15:1–10PubMedCrossRefGoogle Scholar
- Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, Landi S, Boillot C, Monnier S, Chajes V, Clavel-Chapelon F, Tehard B, Chang-Claude J, Linseisen J, Lahmann PH, Pischon T, Trichopoulos D, Trichopoulou A, Zilis D, Palli D, Tumino R, Vineis P, Berrino F, Bueno-de-Mesquita HB, van Gils CH, Peeters PH, Pera G, Ardanaz E, Chirlaque MD, Quiros JR, Larranaga N, Martinez-Garcia C, Allen NE, Key TJ, Bingham SA, Khaw KT, Slimani N, Norat T, Riboli E, Kaaks R (2006) Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer 94:299–307PubMedCrossRefGoogle Scholar
- Cheng I, Penney KL, Stram DO, Le Marchand L, Giorgi E, Haiman CA, Kolonel LN, Pike M, Hirschhorn J, Henderson BE, Freedman ML (2006) Haplotype-based association studies of IGFBP1 and IGFBP3 with prostate and breast cancer risk: the multiethnic cohort. Cancer Epidemiol Biomarkers Prev 15:1993–1997PubMedCrossRefGoogle Scholar
- John EM, Hopper JL, Beck JC, Knight JA, Neuhausen SL, Senie RT, Ziogas A, Andrulis IL, Anton-Culver H, Boyd N, Buys SS, Daly MB, O’Malley FP, Santella RM, Southey MC, Venne VL, Venter DJ, West DW, Whittemore AS, Seminara D (2004) The Breast Cancer Family Registry: an infrastructure for cooperative multinational, interdisciplinary and translational studies of the genetic epidemiology of breast cancer. Breast Cancer Res 6:R375–R389PubMedCrossRefGoogle Scholar
- Pereira JJ, Meyer T, Docherty SE, Reid HH, Marshall J, Thompson EW, Rossjohn J, Price JT (2004) Bimolecular interaction of insulin-like growth factor (IGF) binding protein-2 with alphavbeta3 negatively modulates IGF-I-mediated migration and tumor growth. Cancer Res 64:977–984PubMedCrossRefGoogle Scholar
- Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, Mariotto A, Feuer E, Edwards B (2004) SEER Cancer Statistics Review, 1975–2001. National Cancer Institute, BethesdaGoogle Scholar
- Swanson GM, Lin CS (1994) Survival patterns among younger women with breast cancer: the effects of age, race, stage, and treatment. J Natl Cancer Inst Monogr 69–77Google Scholar