BRCA2, ATM, and CDK12 defects differentially shape prostate tumor driver genomics and clinical aggression

Evan Warner, Cameron Herberts, Simon Fu, Steven Yip, Amanda Wong, Gang Wang, Elie Ritch, Andrew J. Murtha, Gillian Vandekerkhove, Nicolette M. Fonseca, Arkhjamil Angeles, Arshia Beigi, Elena Schonlau, Kevin Beja, Matti Annala, Daniel Khalaf, Kim N. Chi, Alexander W. Wyatt

Research output: Contribution to journalArticleScientificpeer-review

3 Citations (Scopus)


Purpose: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. Experimental Design: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. Results: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. Conclusions: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.

Original languageEnglish
Pages (from-to)1650-1662
Number of pages13
JournalClinical Cancer Research
Issue number6
Publication statusPublished - Mar 2021
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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