Internet Archive Scholar

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

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 (+7 others)
2019 Clinical Cancer Research  

Preserved Fulltext

fulltext thumbnail
Web Archive Capture PDF (1.7 MB)
https://web.archive.org/web/20210716015444/https://clincancerres.aacrjournals.org/content/clincanres/26/5/1114.full.pdf

A copy of this work was available on the public web and has been preserved in the Wayback Machine. The capture dates from 2021; you can also visit the original URL. The file type is application/pdf.

DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because 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 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing
more » ... nd capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC. Sixteen 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 IHC 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 androgen receptor (AR)-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient 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 AR inhibition and inferior survival compared with a control cohort. Hypermutated MMRd mPC 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.
doi:10.1158/1078-0432.ccr-19-1623 pmid:31744831 fatcat:yzyikqa5r5e6tapw3du67jstpm
Citation

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. "Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer." Clinical Cancer Research 26.5 (2019) clincanres.1623.2019