Whole-Exome Sequencing of Germline Variants in Non-
bioinformatics
germline variants
hereditary breast cancer
whole-exome sequencing
Journal
Biomedicines
ISSN: 2227-9059
Titre abrégé: Biomedicines
Pays: Switzerland
ID NLM: 101691304
Informations de publication
Date de publication:
26 Apr 2022
26 Apr 2022
Historique:
received:
23
03
2022
revised:
20
04
2022
accepted:
24
04
2022
entrez:
28
5
2022
pubmed:
29
5
2022
medline:
29
5
2022
Statut:
epublish
Résumé
Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5−10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17−35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.
Identifiants
pubmed: 35625741
pii: biomedicines10051004
doi: 10.3390/biomedicines10051004
pmc: PMC9138793
pii:
doi:
Types de publication
Journal Article
Langues
eng
Subventions
Organisme : CSRD VA
ID : 1
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA265359
Pays : United States
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