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

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.

We performed targeted sequencing of 1615 plasma cell-free DNA samples from 879 metastatic prostate cancer patients. 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.

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 redetected 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.

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.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jan 07 [Epub ahead of print]

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

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Oncology, University of Auckland., 1331 29 St. NW, University of Calgary., Urologic Sciences, Vancouver Prostate Centre., Pathology, British Columbia Cancer Agency., Vancouver Prostate Centre, University of British Columbia., Internal Medicine, University of British Columbia., University of British Columbia., Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre., Vancouver Centre, British Columbia Cancer Agency., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia .

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