Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer. - UroToday

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DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer. Furthermore, since hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools.

We analyzed plasma cell-free DNA targeted sequencing data from 433 metastatic prostate cancer patients with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185× whole exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and immunohistochemistry.

16 patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in MSH2, MSH6, or MLH1, microsatellite instability, and characteristic trinucleotide signatures. CtDNA was concordant with mismatch repair protein immunohistochemistry and DNA sequencing of tumor tissue. Tumor suppressors such as PTEN, RB1, and TP53 were inactivated by mutation rather than copy number loss. Hotspot mutations in oncogenes such as AKT1, PIK3CA and CTNNB1 were common, and the AR ligand binding domain was mutated in 9/16 patients. We observed high intra-patient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to Androgen Receptor inhibition and inferior survival compared to a control cohort.

Hypermutated MMRd metastatic prostate cancer is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Nov 19 [Epub ahead of print]

Elie Ritch, Simon Y F Fu, Cameron Herberts, Gang Wang, Evan W Warner, Elena Schönlau, Sinja Taavitsainen, Andrew J Murtha, Gillian Vandekerkhove, Kevin Beja, Yulia Loktionova, Daniel Khalaf, Ladan Fazli, Igal Kushnir, Cristiano Ferrario, Sebastien Hotte, Matti Annala, Kim N Chi, Alexander W Wyatt

Urologic Sciences, Vancouver Prostate Centre., Department of Medical Oncology, BC Cancer., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Pathology, British Columbia Cancer Agency., Biomeditech Institute, University of Tampere., Vancouver Centre, British Columbia Cancer Agency., The Ottawa Hospital Cancer Centre, University of Ottawa, and Sackler faculty of medicine, Tel Aviv University., Oncology, Lady Davis Insitute and Jewish General Hospital., Hamilton Health Sciences., Faculty of Medicine and Health Technology, Tampere University., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia .

PubMed https://ift.tt/2MK1w8A



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