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Germline pathogenic variants in the MRE11, RAD50, and NBN (MRN) genes in cancer predisposition: A systematic review and meta-analysis
B. Stastna, T. Dolezalova, K. Matejkova, B. Nemcova, P. Zemankova, M. Janatova, P. Kleiblova, J. Soukupova, Z. Kleibl
Language English Country United States
Document type Systematic Review, Meta-Analysis, Journal Article
Grant support
LX22NPO05102
Ministerstvo Školství, Mládeže a Tělovýchovy
NU20-03-00283
Ministerstvo Zdravotnictví České Republiky
RVO-VFN 00064165
Ministerstvo Zdravotnictví České Republiky
SVV260631
Grantová Agentura, Univerzita Karlova
UNCE/24/MED/022
Grantová Agentura, Univerzita Karlova
COOPERATIO
Grantová Agentura, Univerzita Karlova
PubMed
38924040
DOI
10.1002/ijc.35066
Knihovny.cz E-resources
- MeSH
- DNA-Binding Proteins genetics MeSH
- DNA Repair Enzymes genetics MeSH
- Genetic Predisposition to Disease * MeSH
- MRE11 Homologue Protein * genetics MeSH
- Acid Anhydride Hydrolases * genetics MeSH
- Nuclear Proteins * genetics MeSH
- Humans MeSH
- Neoplasms * genetics MeSH
- Cell Cycle Proteins * genetics MeSH
- Germ-Line Mutation * MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
The MRE11, RAD50, and NBN genes encode the MRN complex sensing DNA breaks and directing their repair. While carriers of biallelic germline pathogenic variants (gPV) develop rare chromosomal instability syndromes, the cancer risk in heterozygotes remains controversial. We performed a systematic review and meta-analysis of 53 studies in patients with different cancer diagnoses to better understand the cancer risk. We found an increased risk (odds ratio, 95% confidence interval) for gPV carriers in NBN for melanoma (7.14; 3.30-15.43), pancreatic cancer (4.03; 2.14-7.58), hematological tumors (3.42; 1.14-10.22), and prostate cancer (2.44, 1.84-3.24), but a low risk for breast cancer (1.29; 1.00-1.66) and an insignificant risk for ovarian cancer (1.53; 0.76-3.09). We found no increased breast cancer risk in carriers of gPV in RAD50 (0.93; 0.74-1.16; except of c.687del carriers) and MRE11 (0.87; 0.66-1.13). The secondary burden analysis compared the frequencies of gPV in MRN genes in patients from 150 studies with those in the gnomAD database. In NBN gPV carriers, this analysis additionally showed a high risk for brain tumors (5.06; 2.39-9.52), a low risk for colorectal (1.64; 1.26-2.10) and hepatobiliary (2.16; 1.02-4.06) cancers, and no risk for endometrial, and gastric cancer. The secondary burden analysis showed also a moderate risk for ovarian cancer (3.00; 1.27-6.08) in MRE11 gPV carriers, and no risk for ovarian and hepatobiliary cancers in RAD50 gPV carriers. These findings provide a robust clinical evidence of cancer risks to guide personalized clinical management in heterozygous carriers of gPV in the MRE11, RAD50, and NBN genes.
Department of Biochemistry Faculty of Science Charles University Prague Czech Republic
Department of Genetics and Microbiology Faculty of Science Charles University Prague Czech Republic
References provided by Crossref.org
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