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Clin Cancer Res. 2017 Nov 15;23(22):6863-6874. doi: 10.1158/1078-0432.CCR-17-0955. Epub 2017 Aug 8.

MSH2 Loss in Primary Prostate Cancer.

Author information

1
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
2
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
3
Department of Medicine, Division of Oncology, University of Washington, Seattle, Washington.
4
Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
6
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland. tlotan1@jhmi.edu.

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 CD8+ lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm2; P = 0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r = 0.72, P = 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. Clin Cancer Res; 23(22); 6863-74. ©2017 AACR.

PMID:
28790115
PMCID:
PMC5690834
DOI:
10.1158/1078-0432.CCR-17-0955
[Indexed for MEDLINE]
Free PMC Article

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