A new study reports biallelic mutations in RAD51C in a Fanconi anemia-like disorder, while a second study reports monoallelic mutations in the same gene associated with increased breast cancer risk.
In this study, BRIP1, PALB2, and RAD51C were sequenced for mutations as a result of previously being associated with breast cancer risk due to their role in the double-strand break repair pathway and their close association with BRCA1 and BRCA2.
In addition, in order to resolve whether common RAD51C SNPs are risk factors for breast cancer, we genotyped five tagging single nucleotide polymorphisms, rs12946522, rs304270, rs304283, rs17222691, and rs28363312, all located within the gene, from 993 Finnish breast cancer cases and 871 controls for cancer associated variants.
Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families).
Some of the genes causing the Fanconi anemia (FA) syndrome, such as BRCA2, BRIP1, PALB2, and RAD51C, are associated with high or moderate risk of developing breast cancer.
Consistent with published results from similar follow-up studies, we suggest that RAD51C mutations are rare events among high-risk breast cancer and breast/ovarian cancer families.
Our results confirm that RAD51C is a susceptibility gene for ovarian and BC and that this gene should be screened for mutations in families with multiple BC/OC.
In the Finnish population, we have identified two founder mutations in RAD51C that increase the risk of ovarian cancer but not breast cancer in the absence of ovarian cancer.
Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP1 (FANCJ), PALB2 (FANCN) and RAD51C (FANCO), are associated with moderate BC risk.
There is ongoing debate whether pathogenic RAD51C alterations increase the relative risk for BC in addition to that for OC, which was estimated to be 5.88 (95% confidence interval = 2.91 to 11.88; P = 7.65 × 10(-7)).
Our results support that RAD51C is a rare breast and ovarian cancer susceptibility gene and may contribute to a small fraction of families including breast and ovarian cancer cases and families with only breast cancer.
We enrolled 132 unselected BrC females and 189 cancer-free female subjects to investigate whether common single nucleotide polymorphisms (SNPs) in non-coding regions of RAD51C modulate the risk of BrC, and whether they affect the level of oxidative stress and the extent/characteristics of DNA damage.
Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk.
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.
Large international collaborative studies are needed to quantify the relative risk of RAD51C alterations for BC and to unravel the genetic modifying factors that determine phenotypic variability with respect to cancer site.
These findings provide insight into the mechanism of genomic instability in ERα-positive breast cancer and suggest that individuals with mutations in RAD51C that are exposed to estrogen would be more susceptible to accumulation of DNA damage, leading to cancer progression.