Abstract
Background: A significant proportion of familial and early-onset breast and ovarian cancers occur in individuals without coding mutations of BRCA1 and BRCA2. Aims: We identified genetic variation at 3′-untranslated region (UTR) of BRCA1 in familial and early-onset breast and ovarian cancer patients both with and without BRCA1/2 mutation in the coding regions (BRCA1/2 pos and BRCA1/2 neg), and verified the possible cancer risk factor of the specific 3′-UTR variation using functional analysis. Methods: BRCA1 SNP analysis was screened in 46 patients and 103 unaffected Thais by heteroduplex analysis and DNA sequencing. After chi-square test for the potential cancer association of the specific 3′-UTR genotypes, the functional tests were conducted using several strategies of the luciferase gene expression model. Results: We document the existence of two 3′-UTR polymorphic sites, the 5711+421(G or T) and the 5711+1286(C or T). Frequency of homozygous genotype 5711+421T/T_5711+1286T/T (or T/T-T/T) in the group of BRCA1/2 neg cancer patients was triple of that seen in unaffected persons and showed a significant cancer association (p = 0.007). Functional analysis of these polymorphic sites using luciferase experiments showed an obvious significant reduction in activity associated with the T allele at both sites. Conclusion: These results suggest that the inheritance of specific 3′-UTR polymorphisms may predispose individuals to early-onset or familial breast or ovarian cancer.
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