Dataset Information

Genomic and Clinicopathologic Characterization of ATM-deficient Prostate Cancer.

ABSTRACT:

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.

SUBMITTER: Kaur H

PROVIDER: S-EPMC7501149 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Genomic and Clinicopathologic Characterization of <i>ATM</i>-deficient Prostate Cancer.

Kaur Harsimar H Salles Daniela C DC Murali Sanjana S Hicks Jessica L JL Nguyen Minh M Pritchard Colin C CC De Marzo Angelo M AM Lanchbury Jerry S JS Trock Bruce J BJ Isaacs William B WB Timms Kirsten M KM Antonarakis Emmanuel S ES Lotan Tamara L TL

Clinical cancer research : an official journal of the American Association for Cancer Research 20200721 18

<h4>Purpose</h4>The <i>ATM</i> (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and <i>ATM</i> mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized.<h4>Experimental design</h4>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 <i>ATM</i> mutations and genetically unselected primary pr ...[more]

PMID: 32694154

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