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Metastatic Prostate Cancers with BRCA2 versus ATM Mutations Exhibit Divergent Molecular Features and Clinical

Justin Hwang1,2, Xiaolei Shi2, Andrew Elliott3

  • 1Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, Minnesota.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|May 1, 2023
PubMed
Abstract

Insights

ATM and BRCA2 mutations in metastatic prostate cancer (mPC) impact treatment response. Understanding their distinct molecular features is key for personalized therapy and improved clinical outcomes in mPC patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Metastatic prostate cancer (mPC) patient outcomes vary based on genetic mutations.
  • ATM and BRCA2 mutations influence response to therapies like PARPi inhibitors.

Purpose of the Study:

  • To investigate the molecular differences between ATM- and BRCA2-mutated mPC.
  • To correlate these molecular features with clinical outcomes and guide future treatment strategies.

Main Methods:

  • Analysis of 1,187 mPC tumors, stratified by ATM, BRCA2, other HRR gene mutations, or HRR-proficient status.
  • Gene expression profiling using Limma and real-world overall survival analysis from insurance claims data.

Main Results:

  • BRCA2-mutated mPC showed worse outcomes with AR-targeted therapies in noncastrate settings; both ATM and BRCA2 mutations correlated with worse outcomes in castrate settings.
  • ATM-mutated mPC featured reduced TP53 mutations and CCND1/FGF coamplification.
  • BRCA2-mutated mPC exhibited higher genomic loss-of-heterozygosity, increased tumor mutational burden, and enriched cell-cycle signaling pathways.

Conclusions:

  • ATM and BRCA2 mutations in mPC are linked to distinct molecular profiles and differential clinical outcomes.
  • These unique molecular characteristics can inform therapeutic decisions and the development of novel treatments for mPC.

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