MRE11 – Prostate Cancer Aggressiveness and Predisposition

Emerging evidence implicates rare germline variants in MRE11A (HGNC:7230) as contributors to aggressive prostate cancer (MONDO:0008315). A large two-stage exome sequencing study of 17 546 men (9185 aggressive, 8361 nonaggressive) identified a significant enrichment of deleterious MRE11A alleles in aggressive versus nonaggressive cases (P < .05) and in metastatic disease (PMID:37733366). This case–control analysis supports a role for MRE11A in prostate cancer predisposition and progression, with carriers of rare MRE11A variants comprising up to 5.6% of aggressive and 7.0% of metastatic cases, compared to 2.3% in nonaggressive cases (PMID:37733366).

No familial segregation data are reported for MRE11A in prostate cancer cohorts, and histologic review of advanced prostate adenocarcinoma did not distinguish HRR-mutated tumors (including MRE11A) from HRR-negative cases, underscoring the need for molecular diagnostics (PMID:38278448). One recurrent MRE11A variant observed in primary tumors is c.469A>G (p.Met157Val), originally described in breast and lymphoid malignancies (PMID:11196167). Autosomal dominant inheritance of deleterious alleles is consistent with single-allele burden in adult onset disease.

Functional studies in Saccharomyces cerevisiae demonstrate that phosphoesterase motif mutations in MRE11 disrupt nuclease activity, DNA double-strand break repair, and Mre11–Rad50 interaction, confirming a conserved mechanism of genome maintenance (PMID:9755192). However, direct functional characterization of MRE11A variants in prostate cells is lacking.

There are no reports disputing the association of MRE11A with prostate cancer risk; the negative histopathology correlation reflects limitations of morphology alone rather than absence of genomic effect. Integrating genetic and experimental data suggests that MRE11A haploinsufficiency may underlie increased genomic instability and aggressive tumor behavior.

Key take-home: Rare germline MRE11A variants confer moderate risk for aggressive and metastatic prostate cancer, supporting inclusion of MRE11A in diagnostic gene panels to inform prognosis and PARP-inhibitor eligibility.

References

• Clinical Cancer Research • 2024 • Germline gene panel testing reveals rare deleterious variants in DNA repair genes associated with aggressive and metastatic prostate cancer PMID:37733366
• Human Pathology • 2024 • Histologic patterns in prostatic adenocarcinoma are not predictive of mutations in the homologous recombination repair pathway PMID:38278448
• Genetics • 1998 • Alteration of N-terminal phosphoesterase signature motifs inactivates Saccharomyces cerevisiae Mre11 PMID:9755192

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