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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Fierheller, Caitlin T 
Serruya, Corinne 

Abstract

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.

Description

Keywords

FANCI, Fanconi anemia pathway, TCGA, cancer predisposing gene, hereditary cancer, ovarian cancer, whole exome sequencing, Female, Humans, Fanconi Anemia Complementation Group Proteins, Genes, BRCA2, Genetic Predisposition to Disease, Molecular Biology, Mutation, Ovarian Neoplasms

Journal Title

Genes (Basel)

Conference Name

Journal ISSN

2073-4425
2073-4425

Volume Title

14

Publisher

MDPI AG
Sponsorship
National Institute for Health and Care Research (IS-BRC-1215-20014)