Affiliations: [a] Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Belgrade, Serbia | [b] Spanish National Cancer Research Centre (CNIO), Madrid, Spain
Correspondence:
[*]
Corresponding author: Ana Krivokuca, Department of Experimental Oncology, Institute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia. Tel.: +381 11 2067 284; Fax: +381 11 685 300; E-mail:[email protected]
Abstract:
BACKGROUND:
In 2010 an important finding was published showing that heterozygous
mutations in RAD51C were highly penetrant and were able to confer an increased
risk for breast and ovarian cancers. The role of possible third high
penetrance breast cancer susceptibility gene was assigned to RAD51C. OBJECTIVE:
Because of its rising importance in breast cancer development and the lack
of information about RAD51C in Slavic populations, our goal was to identify
potential population specific mutations in this gene in order to determine
more detailed genetic screening strategy and breast cancer risk assessment. METHODS:
The study included 55 females from Serbian hereditary breast/ovarian cancer
families negative for sequence alterations and large genomic rearrangements
in BRCA1/2 genes. Whole coding region and exon-intron boundaries of RAD51C were
analyzed by dHPLC. All mutations were confirmed by Sanger sequencing. SIFT
and Polyphen were used to predict possible impact of non-synonymous
variants. RESULTS:
We found 5 variants in RAD51C including two missense, one intronic, one in the
5'UTR and one variant in the promoter region of the gene. Three detected
variants are common - c.1-118G>A (rs16943176, MAF = 0,203); c.1-26C>T
(rs12946397, MAF = 0,207) and c.904+34T>C (rs28363318, MAF = 0,186). We detected
two missense variants, c.790G>A (p.Gly264Ser) in exon 5 and c.859A>G
(p.Thr287Ala) in exon 6. Both of them were previously shown to exhibit
reduced protein function but their contribution to cancer risk is still
unknown. CONCLUSIONS:
Although the initial reports implied that RAD51C might be promising candidate for
next high penetrance breast cancer susceptibility gene, lack of confirmation
suggested that RAD51C mutations are not as common as expected. Our study did not
reveal truncating mutations in RAD51C suggesting that other breast cancer
susceptibility genes may account for the increased susceptibility in our
cohort of high-risk BRCA1/2 negative families.
