MSH2 Loss in Primary Prostate Cancer

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 1133 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% (14/1176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9–10) had MSH2 loss compared to 0.4% (5/1042) of tumors with any other scores (p<0.05). 5% (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 bi-allelic 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 to 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 towards higher clonality in cases versus controls. Conclusion 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, where routine screening may be warranted if validated in additional cohorts.

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

“…This has been associated with underlying somatic and germline defects in MMR family constituents (hMSH2, hMSH6, hMSH3, hMLH1, hPMS1 or hPMS2) and is characterized by microsatellite instability (MSI). Besides, inactivation of MMR genes has been shown to predict sensitivity to immunotherapy in metastatic PC, similar to that seen in colorectal carcinoma (CRC) [13,14].…”

Pembrolizumab for a patient with metastatic castration‐resistant prostate cancer with microsatellite instability‐high

“…Among these patients, 8% (7/91) of adenocarcinomas with a Gleason pattern 5 (Gleason score, 9–10) had MSH2 loss. Additionally, two of 43 patients (5%) with neuroendocrine prostate cancer had MSH2 loss . Schweizer et al .…”

“…There have been several reports on the aggressive pathology of MSI‐high prostate cancer. Guedes et al . reported that 1.2% (14/1176) had MSH2 loss in prostate cancer.…”

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8+ tumor‐associated lymphocytes and poor prognosis in prostate cancer

“…The detections of CD3 and CD8 in this report provided evidence for the ‘inflamed tumor’ notion, which is required for an effective immune response. Recently, Keytruda (an antibody targeting PD‐L1/PD‐1 pathway) becomes the first cancer treatment drug approved by FDA for solid tumors with microsatellite instability‐high (MSI‐H) or mismatch repair deficient (dMMR), and prostate tumors with MSH2 loss were found with a higher density of CD8 + infiltrating lymphocytes, suggesting that Keytruda may be a treatment option for patients with prostate cancer with enriched MSH2 loss . However, the small percentage (1.2%) of MSH2 loss may also explain why limited or no response activity of PD‐L1/PD‐1 blockade therapies could be observed in advance prostate cancer.…”

“…Recently, Keytruda (an antibody targeting PD-L1/PD-1 pathway) becomes the first cancer treatment drug approved by FDA for solid tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), 47 and prostate tumors with MSH2 loss were found with a higher density of CD8 + infiltrating lymphocytes, suggesting that Keytruda may be a treatment option for patients with prostate cancer with enriched MSH2 loss. 48 However, the small percentage (1.2%) of MSH2 loss may also explain why limited or no response activity of PD-L1/PD-1 blockade therapies could be observed in advance prostate cancer. Nonetheless, PD-L1 + TANs may be an additional pathology feature to screen patients with prostate cancer who would benefit from anti-PD-L1/PD-1 axis therapies.…”