Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer

H Ballentine Carter, Brian Helfand, Mufaddal Mamawala, Yishuo Wu, Patricia Landis, Hongjie Yu, Kathleen Wiley, Rong Na, Zhuqing Shi, Jacqueline Petkewicz, Sameep Shah, Richard J. Fantus, Kristian Novakovic, Charles B. Brendler, S. Lilly Zheng, William B Isaacs, Jianfeng Xu

Research output: Contribution to journalArticle

Abstract

Background: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). Objective: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). Design, setting, and participants: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. Outcome measurements and statistical analysis: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. Results and limitations: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR) = 1.96 (95% confidence interval [CI] = 1.004–3.84, p = 0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR = 2.74 (95% CI = 1.26–5.96, p = 0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p = 0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3 + 3 at diagnosis to GS ≥4 + 3 (4.1% vs 0.7%, p = 0.01) versus GS 3 + 4 (2.1% vs 0.6%; p = 0.03). Results are limited by the small number of mutation carriers and an intermediate end point. Conclusions: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. Patient summary: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. Men with inherited mutations in DNA repair genes (BRCA1/2 and ATM) have a greater risk of grade reclassification on active surveillance (AS) than those without. Mutation status can help inform decisions for AS.

Original languageEnglish (US)
JournalEuropean Urology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Germ-Line Mutation
Prostatic Neoplasms
Mutation
Neoplasm Grading
DNA Repair
BRCA1 Gene
BRCA2 Gene
Confidence Intervals
Genes
Mutation Rate
Virulence
Guidelines

Keywords

  • Active surveillance
  • ATM
  • BRCA1
  • BRCA2
  • Germline mutations

ASJC Scopus subject areas

  • Urology

Cite this

Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. / Carter, H Ballentine; Helfand, Brian; Mamawala, Mufaddal; Wu, Yishuo; Landis, Patricia; Yu, Hongjie; Wiley, Kathleen; Na, Rong; Shi, Zhuqing; Petkewicz, Jacqueline; Shah, Sameep; Fantus, Richard J.; Novakovic, Kristian; Brendler, Charles B.; Zheng, S. Lilly; Isaacs, William B; Xu, Jianfeng.

In: European Urology, 01.01.2018.

Research output: Contribution to journalArticle

Carter, HB, Helfand, B, Mamawala, M, Wu, Y, Landis, P, Yu, H, Wiley, K, Na, R, Shi, Z, Petkewicz, J, Shah, S, Fantus, RJ, Novakovic, K, Brendler, CB, Zheng, SL, Isaacs, WB & Xu, J 2018, 'Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer', European Urology. https://doi.org/10.1016/j.eururo.2018.09.021
Carter, H Ballentine ; Helfand, Brian ; Mamawala, Mufaddal ; Wu, Yishuo ; Landis, Patricia ; Yu, Hongjie ; Wiley, Kathleen ; Na, Rong ; Shi, Zhuqing ; Petkewicz, Jacqueline ; Shah, Sameep ; Fantus, Richard J. ; Novakovic, Kristian ; Brendler, Charles B. ; Zheng, S. Lilly ; Isaacs, William B ; Xu, Jianfeng. / Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer. In: European Urology. 2018.
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title = "Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer",
abstract = "Background: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). Objective: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). Design, setting, and participants: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. Outcome measurements and statistical analysis: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. Results and limitations: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR) = 1.96 (95{\%} confidence interval [CI] = 1.004–3.84, p = 0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR = 2.74 (95{\%} CI = 1.26–5.96, p = 0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8{\%} and 2.1{\%}, respectively) than in those not reclassified (1.6{\%} and 0.5{\%}, respectively; p = 0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3 + 3 at diagnosis to GS ≥4 + 3 (4.1{\%} vs 0.7{\%}, p = 0.01) versus GS 3 + 4 (2.1{\%} vs 0.6{\%}; p = 0.03). Results are limited by the small number of mutation carriers and an intermediate end point. Conclusions: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. Patient summary: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. Men with inherited mutations in DNA repair genes (BRCA1/2 and ATM) have a greater risk of grade reclassification on active surveillance (AS) than those without. Mutation status can help inform decisions for AS.",
keywords = "Active surveillance, ATM, BRCA1, BRCA2, Germline mutations",
author = "Carter, {H Ballentine} and Brian Helfand and Mufaddal Mamawala and Yishuo Wu and Patricia Landis and Hongjie Yu and Kathleen Wiley and Rong Na and Zhuqing Shi and Jacqueline Petkewicz and Sameep Shah and Fantus, {Richard J.} and Kristian Novakovic and Brendler, {Charles B.} and Zheng, {S. Lilly} and Isaacs, {William B} and Jianfeng Xu",
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language = "English (US)",
journal = "European Urology",
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TY - JOUR

T1 - Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer

AU - Carter, H Ballentine

AU - Helfand, Brian

AU - Mamawala, Mufaddal

AU - Wu, Yishuo

AU - Landis, Patricia

AU - Yu, Hongjie

AU - Wiley, Kathleen

AU - Na, Rong

AU - Shi, Zhuqing

AU - Petkewicz, Jacqueline

AU - Shah, Sameep

AU - Fantus, Richard J.

AU - Novakovic, Kristian

AU - Brendler, Charles B.

AU - Zheng, S. Lilly

AU - Isaacs, William B

AU - Xu, Jianfeng

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). Objective: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). Design, setting, and participants: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. Outcome measurements and statistical analysis: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. Results and limitations: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR) = 1.96 (95% confidence interval [CI] = 1.004–3.84, p = 0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR = 2.74 (95% CI = 1.26–5.96, p = 0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p = 0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3 + 3 at diagnosis to GS ≥4 + 3 (4.1% vs 0.7%, p = 0.01) versus GS 3 + 4 (2.1% vs 0.6%; p = 0.03). Results are limited by the small number of mutation carriers and an intermediate end point. Conclusions: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. Patient summary: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. Men with inherited mutations in DNA repair genes (BRCA1/2 and ATM) have a greater risk of grade reclassification on active surveillance (AS) than those without. Mutation status can help inform decisions for AS.

AB - Background: Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). Objective: To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). Design, setting, and participants: Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. Outcome measurements and statistical analysis: Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. Results and limitations: Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR) = 1.96 (95% confidence interval [CI] = 1.004–3.84, p = 0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR = 2.74 (95% CI = 1.26–5.96, p = 0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p = 0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3 + 3 at diagnosis to GS ≥4 + 3 (4.1% vs 0.7%, p = 0.01) versus GS 3 + 4 (2.1% vs 0.6%; p = 0.03). Results are limited by the small number of mutation carriers and an intermediate end point. Conclusions: Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. Patient summary: Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer. Men with inherited mutations in DNA repair genes (BRCA1/2 and ATM) have a greater risk of grade reclassification on active surveillance (AS) than those without. Mutation status can help inform decisions for AS.

KW - Active surveillance

KW - ATM

KW - BRCA1

KW - BRCA2

KW - Germline mutations

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DO - 10.1016/j.eururo.2018.09.021

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JO - European Urology

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SN - 0302-2838

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