MSH2 Loss in Primary Prostate Cancer

Abstract

<b>Purpose:</b> Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.<b>Experimental Design:</b> 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).<b>Results:</b> 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 (<i>P</i> < 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 <i>MSH2</i> 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 <i>MSH2</i> 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; <i>P</i> = 0.008), and CD8⁺ density was correlated with mutation burden among cases with MSH2 loss (<i>r</i> = 0.72, <i>P</i> = 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.<b>Conclusions:</b> Loss of MSH2 protein is correlated with <i>MSH2</i> 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. <i>Clin Cancer Res; 23(22); 6863-74. ©2017 AACR</i>.