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Precision Medicine and Imaging

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, Ladan Fazli, Igal Kushnir, Cristiano Ferrario, Sebastien Hotte, Matti Annala, Kim N. Chi and Alexander W. Wyatt
Elie Ritch
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Simon Y.F. Fu
2Department of Medical Oncology, BC Cancer, British Columbia, Canada.
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Cameron Herberts
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Gang Wang
2Department of Medical Oncology, BC Cancer, British Columbia, Canada.
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Evan W. Warner
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Elena Schönlau
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Sinja Taavitsainen
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
3Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, Finland.
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Andrew J. Murtha
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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  • ORCID record for Andrew J. Murtha
Gillian Vandekerkhove
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Kevin Beja
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Yulia Loktionova
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Daniel Khalaf
2Department of Medical Oncology, BC Cancer, British Columbia, Canada.
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Ladan Fazli
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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Igal Kushnir
4The Ottawa Hospital Cancer Centre, University of Ottawa, Ottawa, Ontario, Canada.
5Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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Cristiano Ferrario
6Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
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Sebastien Hotte
7Juravinski Cancer Centre, Hamilton, Ontario, Canada.
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Matti Annala
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
3Prostate Cancer Research Center, Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, Finland.
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Kim N. Chi
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
2Department of Medical Oncology, BC Cancer, British Columbia, Canada.
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  • For correspondence: awyatt@prostatecentre.com kchi@bccancer.bc.ca
Alexander W. Wyatt
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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  • For correspondence: awyatt@prostatecentre.com kchi@bccancer.bc.ca
DOI: 10.1158/1078-0432.CCR-19-1623 Published March 2020
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Abstract

Purpose: 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.

Experimental Design: 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 and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC.

Results: 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.

Conclusions: 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.

See related commentary by Schweizer and Yu, p. 981

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:1114–25

  • Received May 17, 2019.
  • Revision received October 10, 2019.
  • Accepted November 15, 2019.
  • Published first November 19, 2019.
  • ©2019 American Association for Cancer Research.
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Clinical Cancer Research: 26 (5)
March 2020
Volume 26, Issue 5
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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, Ladan Fazli, Igal Kushnir, Cristiano Ferrario, Sebastien Hotte, Matti Annala, Kim N. Chi and Alexander W. Wyatt
Clin Cancer Res March 1 2020 (26) (5) 1114-1125; DOI: 10.1158/1078-0432.CCR-19-1623

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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, Ladan Fazli, Igal Kushnir, Cristiano Ferrario, Sebastien Hotte, Matti Annala, Kim N. Chi and Alexander W. Wyatt
Clin Cancer Res March 1 2020 (26) (5) 1114-1125; DOI: 10.1158/1078-0432.CCR-19-1623
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