What is the role of the MRE11 (Meiotic Recombination 11) gene in relation to cancer and disease risk?

MRE11 Gene: Role in DNA Repair and Cancer Risk

MRE11 (Meiotic Recombination 11) is a DNA repair gene that encodes a nuclease protein essential for repairing double-strand DNA breaks as part of the MRE11-RAD50-NBS1 (MRN) complex, and germline mutations in this gene are associated with increased cancer risk, particularly in prostate, breast, and colorectal cancers. 1

Function and Mechanism

DNA Repair Complex:

• MRE11 functions as part of the MRN complex (MRE11-RAD50-NBS1), which detects and repairs DNA double-strand breaks 2
• The protein possesses nuclease activities that are critical for processing damaged DNA and maintaining genomic stability 3
• MRN complex activates the ataxia-telangiectasia mutated (ATM) kinase, triggering cell-cycle checkpoints when DNA damage is detected 3

Cancer Risk and Germline Mutations

Prostate Cancer:

• Germline mutations in MRE11A occur in 11.8% of men with metastatic prostate cancer and 6% of those with high-risk localized disease 1, 4
• MRE11A is included among 16 DNA repair genes with documented germline mutations in metastatic prostate cancer patients 1
• The NCCN recommends genetic testing for MRE11A in patients with metastatic prostate cancer or high-risk localized disease 1

Breast Cancer:

• MRE11 variants, particularly rs684507, are associated with increased breast cancer risk (OR 3.71,95% CI 1.68-8.18) 2
• MRE11 is included in comprehensive cancer gene panels for breast cancer risk assessment 1

Colorectal Cancer:

• MRE11 is frequently inactivated in mismatch repair-deficient colorectal cancers through mutations in a poly(T)11 repeat within intron 4 5
• This mutation leads to aberrant splicing, impaired wild-type MRE11 expression, and generation of truncated protein 5
• Somatic MRE11 mutations accumulate in dMMR CRC tumors due to genomic instability 1

Clinical Implications and Surveillance

Cancer Surveillance Recommendations:

• Annual physical examination with attention to lymphadenopathy and organomegaly for pathogenic RAD50/MRN complex variant carriers 4
• Annual complete blood count to monitor for hematologic malignancies in DNA repair gene mutation carriers 4
• Prostate cancer screening starting at age 40-45 in male carriers 4
• Enhanced breast and ovarian cancer surveillance in female carriers of DNA repair gene mutations 4
• Head and neck cancer screening starting in adolescence with biannual dental examinations and annual otolaryngology evaluation 4

Therapeutic Implications

Treatment Response:

• DNA repair gene mutations, including MRE11, predict response to PARP inhibitors, which show efficacy in tumors with homologous recombination deficiency 4
• Platinum-based chemotherapy demonstrates enhanced response rates in DNA repair-deficient tumors compared to wild-type tumors 4
• MRE11 nuclease activity is required for oncogenesis, and inhibition increases DNA damage selectively in cells overexpressing oncogenes 3

Prognostic Significance:

• Elevated MRE11 expression in prostate cancer tissue is associated with cancer progression and poor survival outcomes 6
• In TCGA cohort, patients with positive MRE11 expression showed poorer overall survival (P=0.019) 6
• MRE11 may serve as a prognostic marker for prostate cancer patients 6

Genetic Counseling Requirements

Immediate Actions:

• Referral to genetic counseling for confirmation of variant pathogenicity 4
• Family cascade testing to identify at-risk relatives 4
• Discussion of reproductive implications for carriers 4

Critical Caveats

Paradoxical Role in Cancer:

• Unlike typical tumor suppressors, MRE11 nuclease activities are actually required for oncogenesis, as they help cancer cells counter oncogene-induced replication stress 3
• Complete MRE11 deficiency prevents tumorigenesis in mouse models predisposed to B-cell lymphomas, even in the absence of p53 3
• This suggests MRE11 inhibition, rather than restoration, may offer therapeutic benefit in established cancers 3

Mismatch Repair Context:

• MRE11 mutations are particularly prevalent in mismatch repair-deficient cancers, where they contribute to genomic instability 5
• The mutation leads to reduced expression of the entire MRN complex, impaired S-phase checkpoint, and abrogation of radiation-induced nuclear foci 5