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Genomic and Clinicopathologic Characterization of ATM-deficient Prostate Cancer
Harsimar Kaur1, Daniela C Salles1, Sanjana Murali1
1Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Purpose:
The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.
Experimental Design:
We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes.
Results:
ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables.
Conclusions:
ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.
Insights
ATM protein loss is more common in high-grade prostate cancers. Evaluating ATM status requires both genomic and IHC tests to guide targeted therapies for these cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The ataxia telangiectasia mutated (ATM) gene is frequently mutated in various cancers, including a subset of prostate cancers.
- ATM deficiency can create specific therapeutic vulnerabilities, but ATM-deficient prostate cancers remain poorly characterized.
- Understanding ATM alterations is crucial for developing targeted treatment strategies in prostate cancer.
Purpose of the Study:
- To genetically validate an immunohistochemistry (IHC) assay for detecting ATM protein loss.
- To determine the frequency of ATM protein loss in primary prostate carcinomas, including those with germline ATM mutations.
- To correlate ATM protein loss with genomic alterations and clinical outcomes in prostate cancer patients.
Main Methods:
- Genetically validated a clinical-grade IHC assay to detect ATM protein loss.
- Examined ATM protein loss frequency in primary prostate tumors using tissue microarrays (TMAs).
- Correlated IHC results with targeted somatic genomic sequencing and analyzed clinical outcomes.
Main Results:
- ATM protein loss was detected in 13% of Gleason pattern 5 cancers and was highly sensitive for biallelic ATM inactivation.
- 74% of patients with pathogenic germline ATM mutations showed ATM protein loss, with most having genomic evidence of biallelic inactivation.
- ATM loss was identified in 3% of all primary tumors, significantly enriched in high-grade (Gleason grade group 5) prostate cancers (9%) compared to lower grades (1%).
Conclusions:
- ATM loss is significantly enriched in high-grade prostate cancers.
- Comprehensive evaluation of ATM status necessitates both genomic and IHC analyses.
- Assessing ATM status is essential for guiding the development of molecularly targeted therapies for prostate cancer.
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