MSH2-deficient prostate tumours have a distinct immune response and clinical outcome compared to MSH2-deficient colorectal or endometrial cancer

Prostate Cancer Prostatic Dis. 2021 Dec;24(4):1167-1180. doi: 10.1038/s41391-021-00379-4. Epub 2021 Jun 9.

Abstract

Background: Recent publications have shown patients with defects in the DNA mismatch repair (MMR) pathway driven by either MSH2 or MSH6 loss experience a significant increase in the incidence of prostate cancer. Moreover, this increased incidence of prostate cancer is accompanied by rapid disease progression and poor clinical outcomes.

Methods and results: We show that androgen-receptor activation, a key driver of prostate carcinogenesis, can disrupt the MSH2 gene in prostate cancer. We screened tumours from two cohorts (recurrent/non-recurrent) of prostate cancer patients to confirm the loss of MSH2 protein expression and identified decreased MSH2 expression in recurrent cases. Stratifying the independent TCGA prostate cancer cohort for MSH2/6 expression revealed that patients with lower levels of MSH2/6 had significant worse outcomes, in contrast, endometrial and colorectal cancer patients with lower MSH2/6 levels. MMRd endometrial and colorectal tumours showed the expected increase in mutational burden, microsatellite instability and enhanced immune cell mobilisation but this was not evident in prostate tumours.

Conclusions: We have shown that loss or reduced levels of MSH2/MSH6 protein in prostate cancer is associated with poor outcome. However, our data indicate that this is not associated with a statistically significant increase in mutational burden, microsatellite instability or immune cell mobilisation in a cohort of primary prostate cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / immunology
  • DNA Mismatch Repair
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / immunology
  • Female
  • Gene Rearrangement
  • Germ-Line Mutation
  • Humans
  • Male
  • Microsatellite Instability
  • MutS Homolog 2 Protein / genetics*
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / immunology
  • Transcriptome
  • Tumor Cells, Cultured
  • Whole Genome Sequencing

Substances

  • MSH2 protein, human
  • MutS Homolog 2 Protein