MSH2 is Inactivated by Multiple Mechanisms in Prostate Tumors, Leading to a Distinct Immune Response and Clinical Outcome Compared to MSH2 Deficient Colorectal Cancer

Patients with defects in the mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer, whilst germline MMR defects in either MLH1 or PMS2, exhibit no such increase. Prostatic carcinogenesis is driven by androgen signalling. Here we show that androgen-receptor activation can disrupt the MSH2 gene in prostate cancer model systems. We screened tumors from two contrasting risk cohorts of prostate cancer patients to confirm loss of MSH2 protein expression and surprisingly found a small but significant fraction of high risk cases exhibited reduced expression of MSH2. Stratifying a large independent TCGA prostate cancer cohort for MSH2 expression levels revealed that patients whose tumors exhibited either complete loss or aberrant levels of MSH2 had equally significant worse survival outcomes and accelerated clinical progression. In contrast, colorectal cancer patients with aberrant MSH2 levels had improved clinical survival. We show that reduced expression of MSH2 can also occur through androgen-induced miRNA regulatory mechanisms. Aberrant MSH2 expression in prostate tumors does not induce enhanced immune cell mobilisation seen in colorectal tumors suggesting that the prostate is an immune privileged site that is less likely to benefit from immunotherapies.