MSH2 Loss in Primary Prostate Cancer.

Area of Science:

• Oncology
• Genetics
• Immunology

Background:

• Mismatch repair (MMR) gene inactivation is implicated in predicting immunotherapy response in metastatic prostate cancer.
• MMR defects in primary prostate tumors are not well-characterized.

Purpose of the Study:

• To investigate the prevalence and characteristics of mismatch repair (MMR) gene defects, specifically MSH2 loss, in primary prostate tumors.
• To determine the association between MSH2 loss and tumor mutational burden, microsatellite instability (MSI), and tumor-infiltrating lymphocytes (TILs).

Main Methods:

• Screening of 1,133 primary prostatic adenocarcinomas and 43 neuroendocrine prostate cancers (NEPC) for MSH2 loss using immunohistochemistry and next-generation sequencing (NGS).
• Assessment of microsatellite instability (MSI) via PCR and NGS (mSINGS).
• Evaluation of CD8+ T-cell density and T-cell receptor clonality in tumors with and without MSH2 loss.

Main Results:

• MSH2 loss was observed in 1.2% of primary prostate tumors, with a higher prevalence in high-grade adenocarcinomas (Gleason score 9-10) and NEPC.
• NGS confirmed MSH2 loss-of-function alterations in all cases, with biallelic inactivation and hypermutation observed in 83% of MSH2-deficient tumors.
• Tumors with MSH2 loss exhibited significantly higher CD8+ T-cell infiltration and a trend toward increased T-cell receptor clonality compared to controls.

Conclusions:

• Loss of MSH2 protein in primary prostate cancer is linked to MSH2 gene inactivation, hypermutation, and increased tumor-infiltrating lymphocytes.
• MSH2 loss is most prevalent in very high-grade primary prostate tumors, suggesting potential utility in routine screening.
• These findings highlight the importance of MMR status in understanding prostate cancer biology and potential immunotherapy response.