Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations

Zsofia Sztupinszki, Miklos Diossy, Marcin Krzystanek, Judit Borcsok, Mark M. Pomerantz, Viktoria Tisza, S. Spisák, Orsolya Rusz, István Csabai, Matthew L. Freedman, Zoltan Szallasi

Research output: Contribution to journalArticle

Abstract

PURPOSE: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. EXPERIMENTAL DESIGN: Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; n = 311) and whole-exome sequencing (WES) data (n = 498) of both primary and metastatic prostate adenocarcinomas to determine whether prostate cancer cases display clear signs of HRD in somatic tumor biopsies. RESULTS: Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. CONCLUSIONS: These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).

Original languageEnglish
Pages (from-to)2673-2680
Number of pages8
JournalClinical Cancer Research
Volume26
Issue number11
DOIs
Publication statusPublished - Jun 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Sztupinszki, Z., Diossy, M., Krzystanek, M., Borcsok, J., Pomerantz, M. M., Tisza, V., Spisák, S., Rusz, O., Csabai, I., Freedman, M. L., & Szallasi, Z. (2020). Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations. Clinical Cancer Research, 26(11), 2673-2680. https://doi.org/10.1158/1078-0432.CCR-19-2135