Abstract
BackgroundA major molecular pathway of genetic instability in cancer is DNA mismatch repair deficiency. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. Data about the prevalence of high-level microsatellite instability in cholangiocarcinoma (CCA) has been conflicting.MethodsWe employed a cohort comprising 308 Western-world, non-liver fluke-associated CCAs (159 intrahepatic, 106 perihilar, and 43 distal). We analysed the mononucleotide microsatellite instability marker panel consisting of BAT25, BAT26, and CAT25 and detected MSI-H in 4/308 CCAs (1.3%).ResultsPatients affected by MSI-H CCA had mostly an atypical histomorphology (p = 0.004), showed a longer overall survival, although having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs.ConclusionsEven though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, particularly in younger patients showing an atypical histomorphology.
Highlights
The incidence of DNA mismatch repair-deficient, microsatelliteunstable tumours is of particular clinical relevance since it has been shown that DNA mismatch repair-deficient tumours are significantly more responsive to immune checkpoint blockade, using antibodies directed against the immune checkpoint Programmed cell Death protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1),[1] than DNA mismatch repairproficient tumours
Frequency of high-level microsatellite instability in cholangiocarcinoma A comprehensive cholangiocarcinoma cohort including all anatomical subtypes has been evaluated for microsatellite instability status
All cases were tested for microsatellite instability status using a highly sensitive mononucleotide marker panel (BAT25, BAT26, CAT25), which detects DNA mismatch repair deficiency.[7,10]
Summary
The incidence of DNA mismatch repair-deficient, microsatelliteunstable tumours is of particular clinical relevance since it has been shown that DNA mismatch repair-deficient tumours are significantly more responsive to immune checkpoint blockade, using antibodies directed against the immune checkpoint Programmed cell Death protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1),[1] than DNA mismatch repairproficient tumours. High-level microsatellite instability (MSI-H) is currently the best predictor of responsiveness towards immune checkpoint blockade. RESULTS: Patients affected by MSI-H CCA had mostly an atypical histomorphology (p = 0.004), showed a longer overall survival, having a high tumour stage, and were of younger age. Correlation analysis of microsatellite instability status with tumour-infiltrating immune cells, MHC I, and PD-L1 expression in the same cholangiocarcinoma cohort showed higher numbers of CD8 + T cells, FOXP3 + regulatory T cells, CD20 + B cells and high or at least moderate MHC I expression levels in MSI-H CCAs. CONCLUSIONS: Even though the overall number of MSI-H CCAs is low, the dismal prognosis of the disease and the therapeutic option of immune checkpoint blockade in the respective patients justify MSI testing of cholangiocarcinoma, in younger patients showing an atypical histomorphology
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