MSH2 loss in primary prostate cancer

Liana B. Guedes, Emmanuel Antonarakis, Michael T. Schweizer, Nooshin Mirkheshti, Fawaz Almutairi, Jong Chul Park, Stephanie Glavaris, Jessica Hicks, Mario Eisenberger, Angelo Michael Demarzo, Jonathan Ira Epstein, William B Isaacs, James Eshleman, Colin C. Pritchard, Tamara Lotan

Research output: Contribution to journalArticle

Abstract

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (P < 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8þ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P ¼ 0.008), and CD8þ density was correlated with mutation burden among cases with MSH2 loss (r ¼ 0.72, P ¼ 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls. Conclusions: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.

Original languageEnglish (US)
Pages (from-to)6863-6874
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Guedes, L. B., Antonarakis, E., Schweizer, M. T., Mirkheshti, N., Almutairi, F., Park, J. C., Glavaris, S., Hicks, J., Eisenberger, M., Demarzo, A. M., Epstein, J. I., Isaacs, W. B., Eshleman, J., Pritchard, C. C., & Lotan, T. (2017). MSH2 loss in primary prostate cancer. Clinical Cancer Research, 23(22), 6863-6874. https://doi.org/10.1158/1078-0432.CCR-17-0955