Abstract
IntroductionMutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. We hypothesized that germline mutations in FANCD2, BRIP1/BACH1, LMO4 and SFN may account for some of the unexplained multiple-case breast cancer families.MethodsThe families used in this study were ascertained through the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Denaturing high performance liquid chromatography (DHPLC) analysis of the coding regions of these four genes was conducted in the youngest affected cases of 30 to 267 non-BRCA1/2 breast cancer families. In addition, a further 399 index cases were also screened for mutations in two functionally significant regions of the FANCD2 gene and 253 index cases were screened for two previously reported mutations in BACH1 (p. P47A and p. M299I).ResultsDHPLC analysis of FANCD2 identified six silent exonic variants, and a large number of intronic variants, which tagged two common haplotypes. One protein truncating variant was found in BRIP1/BACH1, as well as four missense variants, a silent change and a variant in the 3' untranslated region. No missense or splice site mutations were found in LMO4 or SFN. Analysis of the missense, silent and frameshift variants of FANCD2 and BACH1 in relatives of the index cases, and in a panel of controls, found no evidence suggestive of pathogenicity.ConclusionThere is no evidence that highly penetrant exonic or splice site mutations in FANCD2, BRIP1/BACH1, LMO4 or SFN contribute to familial breast cancer. Large scale association studies will be necessary to determine whether any of the polymorphisms or haplotypes identified in these genes contributes to breast cancer risk.
Highlights
Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families
The activated FANCD2 protein is translocated to chromatin and DNA-repair foci, where it co-localises with other DNA repair proteins such as BRCA1, BRCA2, ATM, NBS1 and RAD51 [9]
A subset of the index cases screened for mutations were included in a 10 cM genome-wide search for novel breast cancer susceptibility genes in multiple case breast cancer families from which BRCA1 and BRCA2 mutations had been excluded by high-sensitivity methods and in which no haplotype was shared at either locus
Summary
Mutations in known predisposition genes account for only about a third of all multiple-case breast cancer families. Houghtaling et al [10] showed that FANCD2 homozygous and heterozygous mice display a high incidence of epithelial tumours, including mammary and ovarian carcinomas These mice display other features found in BRCA2 mutant mice, including germ-cell defects, small size, and perinatal lethality [11]. Analysis of the FA genes (FANCA, B, C, D1, D2, E, F, G) in 88 non-BRCA1, non-BRCA2 breast cancer families failed to identify any penetrant mutations, but none of these families were known to share a haplotype around the relevant FANC genes, or to include cases of ovarian cancer [14]
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