FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer.
BRCA1 Protein
/ genetics
BRCA2 Protein
/ genetics
Cell Line, Tumor
Checkpoint Kinase 1
/ genetics
DNA Helicases
/ genetics
Exonucleases
/ genetics
Female
Genetic Predisposition to Disease
/ genetics
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Neoplastic Syndromes, Hereditary
/ genetics
Ovarian Neoplasms
/ genetics
Proto-Oncogene Proteins
/ genetics
RNA Interference
RNA, Small Interfering
/ genetics
Cancer predisposition
Genetic risk
Hereditary breast and ovarian cancer
Journal
Cancer genetics
ISSN: 2210-7762
Titre abrégé: Cancer Genet
Pays: United States
ID NLM: 101539150
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
06
02
2019
revised:
27
03
2019
accepted:
18
04
2019
pubmed:
13
5
2019
medline:
7
3
2020
entrez:
13
5
2019
Statut:
ppublish
Résumé
Although 25% of ovarian cancer cases are due to inherited factors, most of the genetic risk remains unexplained. We previously identified candidate genes through germline whole exome sequencing of BRCA1/BRCA2 negative ovarian cancer patients with familial risk. Here, we performed functional assessment to determine whether they act as BRCA-like tumor suppressors. Seven candidate risk genes were targeted by siRNA for mRNA depletion followed by functional assays for clonogenic survival, cytotoxicity to DNA damaging agents, and involvement in homologous recombination repair. BRCA1 and BRCA1 were targeted as standards for loss of function outcome. Knockdown of various candidate genes led to tumor suppressor phenotypes also observed in BRCA1/BRCA2 deficient cells. Deficiency of CHEK1, FANCM and TP53I3 led to reduced homologous recombination repair efficiency. Knockdown of RAD1, CHEK1 or FANCM led to a decrease in cellular viability and cells deficient in CHEK1, RAD1 or TP53I3 displayed increased sensitivity to cisplatin. Functional studies of candidate genes identified by whole exome sequencing complements bioinformatics techniques and aid the implication of novel risk loci. The results of this study suggest that genes found mutated in hereditary ovarian cancer, FANCM, RAD1, CHEK1 and TP53I3, act as BRCA-like tumor suppressors.
Identifiants
pubmed: 31078449
pii: S2210-7762(19)30037-7
doi: 10.1016/j.cancergen.2019.04.061
pii:
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Intracellular Signaling Peptides and Proteins
0
Proto-Oncogene Proteins
0
RNA, Small Interfering
0
TP53I3 protein, human
0
CHEK1 protein, human
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
Exonucleases
EC 3.1.-
Rad1 protein, human
EC 3.1.11.-
FANCM protein, human
EC 3.6.1.-
DNA Helicases
EC 3.6.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
57-64Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.