RAD51C mutation increases the risk for breast and
ovarian cancer, and was first established as a human cancer susceptibility gene in 2010. Carriers of an RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene. A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15%. In addition, there are three other causes of RAD51C deficiency that also appear to increase cancer risk. These are
alternative splicing,
promoter methylation and repression by over-expression of
EZH2. Three alternatively spliced RAD51C transcripts were identified in colorectal cancers. Variant 1 is joined from the 3' end of exon-6 to the 5' end of exon-8, variant 2 is joined at the 3' end of exon-5 to the 5' end of exon-8, and variant 3 is joined from the 3' end of exon-6 to the 5' end of exon-9. Presence and mRNA expression of variant 1 RAD51C was found in 47% of colorectal cancers. Variant 1 mRNA was expressed about 5-fold more frequently in colorectal tumors than in non-tumor tissues, and when present, was expressed 8-fold more frequently than wild-type RAD51C mRNA. The authors concluded that variant 1 mRNA was associated with the malignant phenotype of colorectal cancers On the other hand, methylation of the RAD51C promoter was only found in about 1.5% of ovarian cancer cases. EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% and 75% of breast cancers have over-expressed EZH2 protein. EZH2 is the catalytic subunit of
polycomb repressive complex 2 (PRC2) which
catalyzes methylation of
histone H3 at lysine 27 (
H3K27me) and mediates
epigenetic gene silencing of target genes via local
chromatin reorganization. Increased expression of EZH2, leading to repression of RAD51 paralogs and consequent reduced
homologous recombinational repair, was proposed as a cause of breast cancer. == Interactions ==