Germline pathogenic variants in the MRE11, RAD50, and NBN (MRN) genes in cancer predisposition: A systematic review and meta-analysis.

in International journal of cancer by Barbora Stastna, Tatana Dolezalova, Katerina Matejkova, Barbora Nemcova, Petra Zemankova, Marketa Janatova, Petra Kleiblova, Jana Soukupova, Zdenek Kleibl

TLDR

  • The study looked at the risk of cancer in people who have a certain genetic mutation in one of three genes. The study found that people with this mutation had a higher risk of certain types of cancer, but a lower risk of others. The study also looked at how often this mutation was found in different groups of people and found that it was more common in some groups than others. These findings can help doctors better understand the risk of cancer in people with this mutation and make personalized treatment plans for them.

Abstract

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.

Overview

  • The study aims to understand the cancer risk in heterozygotes of biallelic germline pathogenic variants (gPV) in the MRE11, RAD50, and NBN genes, which encode the MRN complex sensing DNA breaks and directing their repair. The study performed a systematic review and meta-analysis of 53 studies in patients with different cancer diagnoses to better understand the cancer risk in heterozygotes of gPV in these genes. The primary objective of the study is to provide robust clinical evidence of cancer risks to guide personalized clinical management in heterozygous carriers of gPV in the MRE11, RAD50, and NBN genes.

Comparative Analysis & Findings

  • The study found an increased risk for gPV carriers in NBN for melanoma, pancreatic cancer, hematological tumors, and prostate cancer, but a low risk for breast cancer and an insignificant risk for ovarian cancer. The study also found no increased breast cancer risk in carriers of gPV in RAD50 and MRE11. 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, a low risk for colorectal and hepatobiliary cancers, and no risk for endometrial and gastric cancer. The secondary burden analysis showed also a moderate risk for ovarian cancer 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.

Implications and Future Directions

  • The study's 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. The study identifies an increased risk for gPV carriers in NBN for melanoma, pancreatic cancer, hematological tumors, and prostate cancer, but a low risk for breast cancer and an insignificant risk for ovarian cancer. The study also found no increased breast cancer risk in carriers of gPV in RAD50 and MRE11. The secondary burden analysis compared the frequencies of gPV in MRN genes in patients from 150 studies with those in the gnomAD database. The study identifies a high risk for brain tumors, a low risk for colorectal and hepatobiliary cancers, and no risk for endometrial and gastric cancer in NBN gPV carriers. The study also identifies a moderate risk for ovarian cancer in MRE11 gPV carriers, and no risk for ovarian and hepatobiliary cancers in RAD50 gPV carriers. These findings suggest that heterozygous carriers of gPV in the MRE11, RAD50, and NBN genes should undergo personalized clinical management to monitor for an increased risk of cancer. Future research should focus on identifying the mechanisms underlying the increased cancer risk in gPV carriers of the MRE11, RAD50, and NBN genes and developing targeted interventions to prevent or manage cancer in these individuals.
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