TY - JOUR
T1 - MSH2-deficient prostate tumours have a distinct immune response and clinical outcome compared to MSH2-deficient colorectal or endometrial cancer
AU - McCoy, Patrick
AU - Mangiola, Stefano
AU - Macintyre, Geoff
AU - Hutchinson, Ryan
AU - Tran, Ben
AU - Pope, Bernard
AU - Georgeson, Peter
AU - Hong, Matthew K. H.
AU - Kurganovs, Natalie
AU - Lunke, Sebastian
AU - Clarkson, Michael J.
AU - Cmero, Marek
AU - Kerger, Michael
AU - Stuchbery, Ryan
AU - Chow, Ken
AU - Haviv, Izhak
AU - Ryan, Andrew
AU - Costello, Anthony J
AU - Corcoran, Niall M.
AU - Hovens, Christopher M.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Cancer genetics
KW - Prostate cancer
U2 - 10.1038/s41391-021-00379-4
DO - 10.1038/s41391-021-00379-4
M3 - Article
SN - 1365-7852
VL - 24
SP - 1167
EP - 1180
JO - PROSTATE CANCER AND PROSTATIC DISEASES
JF - PROSTATE CANCER AND PROSTATIC DISEASES
IS - 4
ER -