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, Wei Fu, Hao Wang, Alexander Baras, Tamara Lotan, Emmanuel Antonarakis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalProstate Cancer and Prostatic Diseases
DOIs
StateAccepted/In press - Jan 1 2018

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Neoplasm Grading
DNA Repair
Prostatic Neoplasms
Mutation
Genes
Neoplasms
Recombinational DNA Repair
Prostate
Adenocarcinoma
Odds Ratio
Clinical Trials
DNA

ASJC Scopus subject areas

  • Oncology
  • Urology
  • Cancer Research

Cite this

@article{4ba3ece9ccf644b581b76c41d37d938e,
title = "Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features: association of Gleason score and tumor stage",
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.",
author = "Marshall, {Catherine Handy} and Wei Fu and Hao Wang and Alexander Baras and Tamara Lotan and Emmanuel Antonarakis",
year = "2018",
month = "1",
day = "1",
doi = "10.1038/s41391-018-0086-1",
language = "English (US)",
journal = "Prostate Cancer and Prostatic Diseases",
issn = "1365-7852",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Prevalence of DNA repair gene mutations in localized prostate cancer according to clinical and pathologic features

T2 - association of Gleason score and tumor stage

AU - Marshall, Catherine Handy

AU - Fu, Wei

AU - Wang, Hao

AU - Baras, Alexander

AU - Lotan, Tamara

AU - Antonarakis, Emmanuel

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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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U2 - 10.1038/s41391-018-0086-1

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