Background BRIP1 interacts with BRCA1 and functions in regulating DNA double strand break repair pathways. Germline BRIP1 mutations are associated with breast cancer and Fanconi anemia. Thus, common variants in the BRIP1 are candidates for breast and ovarian cancer susceptibility. Methods We used a SNP tagging approach to evaluate the association between common variants (minor allele frequency≥0.05) in BRIP1 and the risks of breast cancer and invasive ovarian cancer. 12 tagging SNPs (tSNPs) in the gene were identified and genotyped in up to 2,270 breast cancer cases and 2,280 controls from the UK and up to 1,513 invasive ovarian cancer cases and 2,515 controls from the UK, Denmark and USA. Genotype frequencies in cases and controls were compared using logistic regression. Results Two tSNPs showed a marginal significant association with ovarian cancer: Carriers of the minor allele of rs2191249 were at reduced risk compared with the common homozygotes (Odds Ratio (OR) = 0.90 (95% CI, 0.82–1.0), P-trend = 0.045) and the minor allele of rs4988344 was associated with increased risk (OR = 1.15 (95%CI, 1.02–1.30), P-trend = 0.02). When the analyses were restricted to serous ovarian cancers, these effects became slightly stronger. These results were not significant at the 5% level after adjusting for multiple testing. None of the tSNPs was associated with breast cancer. Conclusions It is unlikely that common variants in BRIP1 contribute significantly to breast cancer susceptibility. The possible association of rs2191249 and rs4988344 with ovarian cancer risks warrant confirmation in independent case-control studies.
References
[1]
Lynch HT, Casey MJ, Lynch J, White TE, Godwin AK (1998) Genetics and ovarian carcinoma. Semin.Oncol, 25: 265–280.
[2]
Rahman N, Stratton MR (1998) The genetics of breast cancer susceptibility. Annu Rev Genet, 32: 95–121.
[3]
Easton DF (1999) How many more breast cancer predisposition genes are there? Breast Cancer Res, 1: 14–17.
[4]
Pharoah PD, Ponder BA (2002) The genetics of ovarian cancer. Best Pract.Res Clin Obstet Gynaecol., 16: 449–468.
[5]
Smith P, McGuffog L, Easton DF, Mann GJ, Pupo GM, et al. (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer. 45: 646–55.
[6]
Antoniou AC, Gayther SA, Stratton JF, Ponder BA, Easton DF (2000) Risk models for familial ovarian and breast cancer. Genet Epidemiol. Feb; 18(2): 173–90.
[7]
Cantor SB, Bell DW, Ganesan S, Kass EM, Drapkin R, et al. (2001) BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell, 105: 149–160.
[8]
Levitus M, Waisfisz Q, Godthelp BC, de Vries Y, Hussain S, et al. (2005) The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet, 37: 934–935.
[9]
Cantor S, Drapkin R, Zhang F, Lin Y, Han J, et al. (2004) The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc Natl Acad.Sci.U.S.A, 101: 2357–2362.
[10]
Yu X, Chini CC, He M, Mer G, Chen J (2003) The BRCT domain is a phospho-protein binding domain. Science, 302: 639–642.
[11]
Levran O, Attwooll C, Henry RT, Milton KL, Neveling K, et al. (2005) The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat Genet, 37: 931–933.
[12]
Seal S, Thompson D, Renwick A, Elliott A, Kelly P, et al. (2006) Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat.Genet.
[13]
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, et al. (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science, 250: 1684–1689.
[14]
Callahan R (1998) Somatic mutations that contribute to breast cancer. Biochem Soc Symp., 63: 211–221.
[15]
Chen KC, Hsieh TT, Schwartz PE, Yang-Feng TL (1995) Allelic deletion mapping of putative tumor suppressor genes on 17q in sporadic ovarian cancer. J Obstet Gynaecol, 21: 619–624.
[16]
Garcia-Closas M, Egan KM, Newcomb PA, Brinton LA, Titus-Ernstoff L, et al. (2006) Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses. Hum Genet.
[17]
Lei H, Vorechovsky I (2003) BACH1 517C–>T transition impairs protein translocation to nucleus: a role in breast cancer susceptibility? Int J Cancer, 104: 389–391.
[18]
Lewis AG, Flanagan J, Marsh A, Pupo GM, Mann G, et al. (2005) Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer. Breast Cancer Res, 7: R1005–R1016.
[19]
Rutter JL, Smith AM, Davila MR, Sigurdson AJ, Giusti RM, et al. (2003) Mutational analysis of the BRCA1-interacting genes ZNF350/ZBRK1 and BRIP1/BACH1 among BRCA1 and BRCA2-negative probands from breast-ovarian cancer families and among early-onset breast cancer cases and reference individuals. Hum Mutat., 22: 121–128.
[20]
Sigurdson AJ, Hauptmann M, Chatterjee N, Alexander BH, Doody MM, et al. (2004) Kin-cohort estimates for familial breast cancer risk in relation to variants in DNA base excision repair, BRCA1 interacting and growth factor genes. BMC. Cancer, 4: 9.
[21]
Vahteristo P, Yliannala K, Tamminen A, Eerola H, Blomqvist C, et al. (2006) BACH1 Ser919Pro variant and breast cancer risk. BMC Cancer, 6: 19.
[22]
Song H, Ramus S, Quaye L, DiCioccio R, Tyrer J, et al. (2006) Common variants in mismatch repair genes and risk of invasive ovarian cancer. Carcinogenesis. doi:10.1093/carcin/bgl089.
[23]
de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, et al. (2005) Efficiency and power in genetic association studies. Nat Genet, 37: 1217–1223.
[24]
Zaykin DV, Westfall PH, Young SS, Karnoub MA, Wagner MJ, et al. (2002) Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Hum Hered., 53: 79–91.
[25]
Altshuler D, Brooks LD, Chakravarti A, Collins FS, Daly MJ, et al. (2005) A haplotype map of the human genome. Nature, 437: 1299–1320.
[26]
Luo L, Lei H, Du Q, von Wachenfeldt A, Kockum I, et al. (2002) No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast-cancer families linked to 17q22. Int J Cancer, 98: 638–639.
