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

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)
Pages (from-to)743-749
Number of pages7
JournalEuropean Urology
Volume75
Issue number5
DOIs
StatePublished - May 2019

Keywords

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

ASJC Scopus subject areas

  • Urology

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    Carter, H. B., Helfand, B., Mamawala, M., Wu, Y., Landis, P., Yu, H., Wiley, K., Na, R., Shi, Z., Petkewicz, J., Shah, S., Fantus, R. J., Novakovic, K., Brendler, C. B., Zheng, S. L., Isaacs, W. B., & Xu, J. (2019). Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer(Figure presented.). European Urology, 75(5), 743-749. https://doi.org/10.1016/j.eururo.2018.09.021