ATM – Prostate Cancer

Prostate cancer predisposition due to germline ATM mutations follows an autosomal dominant inheritance pattern with moderate penetrance. Carriers of likely pathogenic ATM variants have a 4.4-fold increased risk of prostate cancer (OR 4.4; 95% CI 2.0–9.5) in a cohort of 5 560 cases and 3 353 controls (PMID:33436325). In men with metastatic disease, 1.6% harbored germline ATM mutations among 692 unselected patients, significantly exceeding rates in localized cases (PMID:27433846).

Genomic analyses have identified >50 distinct ATM pathogenic variants in prostate cancer, including truncating and missense changes, with recurrent hotspots such as c.7271T>G (p.Val2424Gly) (PMID:33436325). In tissue microarray studies, ATM protein loss was observed in 74% of tumors with germline ATM mutations, and 100% sensitivity for biallelic inactivation in high-grade Gleason 5 cases (PMID:32694154). Clinical series report germline ATM mutations in 0.5–1% of advanced prostate cancer patients, often with strong family histories of breast, pancreatic, and gastric cancers (PMID:37284046).

Segregation data are limited, but individual pedigrees demonstrate co-segregation of truncating ATM alleles with early-onset or lethal prostate cancer. Case–control cohorts further support association: a PRACTICAL study of European ancestry cases vs. controls showed odds ratios of 4.4 for tier 1 variants and 1.4 for tier 2 variants (PMID:33436325).

Functional studies confirm ATM’s role in DNA damage response and prostate carcinogenesis. ATM phosphorylates key substrates such as Nbs1 and p95/nbs1 in ATM-deficient models, linking ATM loss to defective double-strand break repair and genomic instability (PMID:10802669). ATM missense mutants (e.g., p.Val2424Gly) act dominantly to abrogate kinase activity, leading to radiosensitivity and checkpoint failure in cell models (PMID:11805335).

Conflicting data exist for common ATM polymorphisms: the 3161C>G (p.Pro1054Arg) variant showed modest association (OR 2.13) in one risk study but no significant risk increase in others (PMID:15280931). Ethnic-specific analyses suggest variable prevalence across populations, underscoring the importance of population-tailored risk assessment (PMID:31248605).

In summary, germline ATM pathogenic variants confer a strong, autosomal dominant predisposition to prostate cancer, especially aggressive and early-onset forms. Functional concordance between human tumors and experimental models supports a haploinsufficiency mechanism. Genetic testing for ATM should be integrated into clinical assessment for men with high-grade or familial prostate cancer to guide surveillance and therapy selection.

Key Take-home: Pathogenic ATM variants are strong predictors of prostate cancer risk and support targeted genetic screening for precision management.

References

• The New England Journal of Medicine • 2016 • Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer PMID:27433846
• European Urology Oncology • 2021 • Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study PMID:33436325
• Clinical Cancer Research • 2020 • Genomic and Clinicopathologic Characterization of ATM-deficient Prostate Cancer PMID:32694154
• Nature Genetics • 2000 • ATM-dependent phosphorylation of nibrin in response to radiation exposure PMID:10802669
• Proceedings of the National Academy of Sciences USA • 2002 • Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer PMID:11805335

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