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. 2019 Mar;22(1):59-65.
doi: 10.1038/s41391-018-0086-1. Epub 2018 Aug 31.

Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

Catherine Handy Marshall  1 , Wei Fu  1 , Hao Wang  1 , Alexander S Baras  2 , Tamara L Lotan  2 , Emmanuel S Antonarakis  3
Affiliations

Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage

Catherine Handy Marshall et al. Prostate Cancer Prostatic Dis. 2019 Mar.

Abstract

Background: DNA repair gene mutations are present in 8-10% of localized prostate cancers. It is unknown whether this is influenced by clinicopathologic factors.

Methods: We interrogated localized prostate adenocarcinomas with tumor DNA sequencing information from the TCGA validated (n = 333) and Nature Genetics (n = 377) datasets. Homologous recombination repair genes included in our analysis were: ATM, BRCA1/2, CDK12, CHEK1/2, FANCA, FANCD2, FANCL, GEN1, NBN, PALB2, RAD51, and RAD51C. Proportions of cases with pathogenic DNA repair mutations (and in ATM/BRCA1/2 specifically) were reported by Gleason grade group, clinical T, pathologic T, and pathologic N stage. Odds ratios and Fisher's exact tests were used to compare proportions between categories.

Results: Patients with Gleason grade groups 3 and higher were 2.2 times more likely to harbor any DNA repair mutation (95% CI: 1.2-4.2; 10.3% versus 5.0%) and were 2.7 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.3-6.6; 7.0% versus 2.7%) compared to those in Gleason grade groups 1-2. Patients with pathologic T3 and T4 stage (pT3/pT4) were 2.6 times more likely to have any DNA repair mutation (95% CI: 1.3-6.6; 13.0% versus 5.5%) and were 3.2 times more likely to have BRCA1/2 or ATM mutations (95% CI: 1.2-11.3; 9.5% versus 3.1%) compared to those with pT2 disease. There was no difference by clinical tumor or nodal stage. Among men with Gleason grade group ≥ 3 and clinical stage ≥ cT3, 21.3% (1 in 5) had a DNA repair mutation in any gene and 11.7% (1 in 9) had a mutation in ATM/BRCA1/2.

Conclusions: The prevalence of pathogenic DNA repair gene alterations is enriched in men with advanced tumor stages and higher Gleason grade groups, with maximal enrichment observed in those with Gleason grade group ≥ 3 and clinical stage ≥ cT3 disease. This information can be used to guide eligibility criteria for genomically targeted clinical trials in the neoadjuvant/adjuvant settings.

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Conflict of interest statement

Disclosures/Conflicts of Interest: Emmanuel S. Antonarakis is a paid consultant/advisor to Janssen, Astellas, Sanofi, Medivation, ESSA, AstraZeneca, Clovis and Merck; he has received research funding to his institution from Janssen, Johnson & Johnson, Sanofi, Genentech, Novartis, Tokai, Bristol Myers-Squibb, AstraZeneca, Clovis and Merck; and he is the co-inventor of a biomarker technology that has been licensed to Tokai and Qiagen. Catherine Handy Marshall received research support through the Conquer Cancer Foundation/Bristol Meyers Squibb.

Figures

Figure 1.
Figure 1.
Percentage of patients with DNA repair gene mutations, overall and according to each individual gene
Figure 2.
Figure 2.
Prevalence of DNA repair mutation by Gleason Grade Group
See this image and copyright information in PMC

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