Celia M. T. Greenwood

The Genetic and Molecular Analyses of Rare Candidate Germline BRIP1/FANCJ Variants Implicated in Hereditary Breast and Ovarian Cancers

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC.

Molecular Genetic Characteristics of FANCI, a Proposed New Ovarian Cancer Predisposing Gene

FANCI was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of FANCI c.1813C>T; p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of FANCI, as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery FANCI c.1813C>T; p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, and FANCI, which identified four candidate variants. We then investigated FANCI in high-grade serous ovarian carcinoma (HGSC) from FANCI c.1813C>T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from FANCI c.1813C>T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as BRCA1 and BRCA2 are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline FANCI c.1813C>T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls (p = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in FANCI that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying FANCI c.1813C>T; p.L605F and suggest the possible involvement of FANCI in other cancer types at the germline and/or somatic level.