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FANCM, RAD1, CHEK1 and TP53I3 act as BRCA-like tumor suppressors and are mutated in hereditary ovarian cancer.
- Source :
-
Cancer genetics [Cancer Genet] 2019 Jun; Vol. 235-236, pp. 57-64. Date of Electronic Publication: 2019 May 09. - Publication Year :
- 2019
-
Abstract
- 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.<br /> (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Subjects :
- BRCA1 Protein genetics
BRCA2 Protein genetics
Cell Line, Tumor
Female
Genetic Predisposition to Disease genetics
HeLa Cells
Humans
RNA Interference
RNA, Small Interfering genetics
Checkpoint Kinase 1 genetics
DNA Helicases genetics
Exonucleases genetics
Intracellular Signaling Peptides and Proteins genetics
Neoplastic Syndromes, Hereditary genetics
Ovarian Neoplasms genetics
Proto-Oncogene Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2210-7762
- Volume :
- 235-236
- Database :
- MEDLINE
- Journal :
- Cancer genetics
- Publication Type :
- Academic Journal
- Accession number :
- 31078449
- Full Text :
- https://doi.org/10.1016/j.cancergen.2019.04.061