Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families

The entire coding region and splice junctions of RNF8, UBC13 and MMS2 genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing.Mutation analysis revealed several changes in RNF8 and UBC13, whereas no aberrations were observed in MMS2. None of the found sequence changes appeared to associate with breast cancer susceptibility.The present data suggest that mutations in RNF8, UBC13 and MMS2 genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.Breast cancer is the most frequent malignancy among women [1], and the presence of a family history is one of the most fundamental risk factors for the disease [2]. Currently known susceptibility genes including BRCA1, BRCA2, ATM, CHEK2, PALB2, RAD51C and BRIP1 explain less than 25% of familial breast cancer. The rest of the cases could be explained by mutations in mainly moderate and low penetrance cancer susceptibility genes together with environmental factors. Many of the genes already associated with breast cancer susceptibility encode proteins that operate together with BRCA1 and BRCA2 in the DNA damage response pathway (DDR) [3-7]. Other genes with similar functions thus represent good candidates for being new susceptibility genes.Recent evidence indicates ubiquitin chain formation, recognition and breakdown at the site of DNA double-strand breaks (DSB) as an essential component of the DDR [8]. RNF8 is a RING-finger ubiquitin ligase (E3), which is recruited to the sites of DNA damage after ATM/ATR-dependent phoshorylation of the H2AX histone variant [9-11]. Together with its ubiquitin-conjugating enzyme (E2) partner UBC13 it mediates K63-linked polyubiquitin conjugation to histones H2A and H2AX. The RNF8/UBC13-dependent histone ubiquitylation is then amplified by the RNF168 E3-ligase acting in concert with UBC13 [12]. Ub