The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer

Dorra BenAyed-Guerfali; Chamseddine Kifagi; Wala BenKridis-Rejeb; Nihel Ammous-Boukhris; Wajdi Ayedi; Afef Khanfir; Jamel Daoud; Raja Mokdad-Gargouri

doi:10.3390/genes13081296

The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer

Genes (Basel). 2022 Jul 22;13(8):1296. doi: 10.3390/genes13081296.

Authors

Dorra BenAyed-Guerfali¹, Chamseddine Kifagi¹, Wala BenKridis-Rejeb², Nihel Ammous-Boukhris¹, Wajdi Ayedi¹, Afef Khanfir², Jamel Daoud³, Raja Mokdad-Gargouri¹

Affiliations

¹ Center of Biotechnology of Sfax, University of Sfax, Sidi Mansour Street Km 6, BP 1177, Sfax 3038, Tunisia.
² Department of Medical Oncology, Habib Bourguiba Hospital, Sfax 3002, Tunisia.
³ Department of Radiotherapy, Habib Bourguiba Hospital, Sfax 3002, Tunisia.

Abstract

(1) Background: Germline variants in BRCA1/BRCA2 genes explain about 20% of hereditary breast/ovarian cancer (HBOC) cases. In the present paper, we aim to identify genetic determinants in BRCA-negative families from the South of Tunisia. (2) Methods: Exome Sequencing (ES) was performed on the lymphocyte DNA of patients negative for BRCA mutations from each Tunisian family with a high risk of HBOC. (3) Results: We focus on the canonical genes associated with HBOC and identified missense variants in DNA damage response genes, such as ATM, RAD52, and RAD54; however, no variants in PALB2, Chek2, and TP53 genes were found. To identify novel candidate genes, we selected variants harboring a loss of function and identified 17 stop-gain and 11 frameshift variants in genes not commonly known to be predisposed to HBOC. Then, we focus on rare and high-impact genes shared by at least 3 unrelated patients from each family and selected 16 gene variants. Through combined data analysis from MCODE with gene ontology and KEGG pathways, a short list of eight candidate genes (ATM, EP300, LAMA1, LAMC2, TNNI3, MYLK, COL11A2, and LAMB3) was created. The impact of the 24 selected genes on survival was analyzed using the TCGA data resulting in a selection of five candidate genes (EP300, KMT2C, RHPN2, HSPG2, and CCR3) that showed a significant association with survival. (4) Conclusions: We identify novel candidate genes predisposed to HBOC that need to be validated in larger cohorts and investigated by analyzing the co-segregation of selected variants in affected families and the locus-specific loss of heterozygosity to highlight their relevance for HBOC risk.

Keywords: BRCA1/BRCA2 genes; candidate genes; exome sequencing; germline variants; hereditary breast/ovarian cancer; pathogenic variants.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / genetics
Exome
Exome Sequencing
Female
Genetic Predisposition to Disease
Humans
Ovarian Neoplasms* / genetics

Supplementary concepts

Breast Cancer, Familial

Grants and funding

This work was supported by a grant from the CIC (Centre d’Investigation Clinique) and The Ministry of Higher Education and Scientific Research of Tunisia (grant: LR19CBS02).