Mutations in the DNA helicase BRIP1
have been implicated in the aetiology of Fanconi anaemia, a genetic disorder that is characterised by congenital abnormalities, progressive bone marrow failure, genomic instability and predisposition to cancer [5
]. Our study assessed the relevance of the BRIP1 variants -64G>A and Pro919Ser to familial BC. According to transcription factor binding site searches, the replacement of G by A at position -64 leads to the formation of a GATA or CCAAT motif, suggesting an modification of gene expression. BRIP Pro919Ser is located in the BRCA1-interacting domain and may alter protein structure and function.
Genotype frequencies for the analysed polymorphisms were in agreement with Hardy-Weinberg expectations in controls. No significant differences in genotype frequencies between BC cases and controls for either BRIP1 -64G>A or Pro919Ser were observed (see Table ). Adjustment for age made no significant difference to the results, hence only unadjusted ORs are presented. Our findings are in accord with previously published data [8
]. Though a recent kin-cohort study has shown a strong association with 4.5- to 6.9-fold familial BC risk for Pro919Ser in premenopausal women [12
], our data do not support the observed effect when stratified according to age at diagnosis (see Table ). Haplotype analysis with BRIP1 -64G>A and Pro919Ser did not indicate any association with familial BC risk (data not shown).
Genotype distributions of the BRIP1 variants -64G>A (rs2048718§) and Pro919Ser (rs4986764§) among unrelated German BRCA1/2 mutation-negative familial breast cancer patients and healthy, unrelated female control subjects
The strengths of the present study are represented by a sound sample size and a homogeneous study cohort of a single ethnic group, comprising women selected for familial BC. Only BRCA1
mutation-negative familial BC cases were considered in order to avoid effects caused by these high-penetrance susceptibility genes. With the present sample size, we had a power of 80% at a significance level of 0.05 to detect an OR of ≥ 1.44 for both -64G>A and Pro919Ser. Moreover, the power of an association study based on cases with a family history of the disease is at least twice higher compared to a study using unselected cases [18
]. As data of well-known risk factors (age of menarche, history of pregnancy etc.) were not available, we ignored to test for gene-environment interaction.