A decade of RAD51C/D: Germline pathogenic variants and their phenotypic landscape

Defects in DNA repair genes have been extensively associated to cancer susceptibility. Germline pathogenic variants (GPV) in genes involved in homologous recombination repair pathway predispose to cancers arising mainly in breast and ovary, but also other tissues. The RAD51 paralogs RAD51C and RAD51D were included in this group 10 years ago, when germline variants were associated to non-BRCA1/2 familial ovarian cancer. However, whether GPVs in these genes are associated with other cancers remains unknown. Here, we have reviewed the landscape of RAD51C and RAD51D germline variants in cancer reported in the literature during the last decade, curating a total of 341 variants and the phenotypes found in families with RAD51C/D variant carriers. A comprehensive catalogue has been generated pinpointing to the existence of recurrent variants in both genes. Investigation of pedigrees found fourteen other cancer types reported more than five times in families with carriers of RAD51C/D pathogenic variants. Among those, colorectal (3.72% and 4.43%) (RAD51C/D respectively), pancreatic (1.19% and 0.86%), lung (1.27% and 2.58%), prostate (1.56% and 1.48%), and leukemia (1.56% and 1.11%) cancer were the most prevalent types. This work highlights how both genes might confer susceptibility to a broader spectrum of cancer types than ovary and breast.

The genetic analysis of a founder Northern American population of European descent identifies FANCI as a candidate familial ovarian cancer risk gene

Some familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC (ρ=0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

Transmission of X-linked Ovarian Cancer: Characterization and Implications

We recently reported evidence that a strong, BRCA-independent locus on the X-chromosome may contribute to ovarian cancer predisposition in families ascertained from the Familial Ovarian Cancer Registry (Buffalo, NY, USA). While it has been estimated that approximately 20% of all ovarian cancer cases are hereditary, it is possible that a significant proportion of cases previously believed to be sporadic may, in fact, be X-linked. Such X-linked disease has a distinct pattern; it implies that a father will necessarily pass a risk allele to each of his daughters, increasing the prevalence of cancers clustered within a family. X-chromosome inactivation further influences the expression of X-linked alleles and may represent a novel target for screening and therapy. Herein, we review the current literature regarding X-linked ovarian cancer and interpret allele transmission-based models to characterize X-linked ovarian cancer and develop a framework for clinical and epidemiological familial ascertainment to inform the design of future studies.