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Staining more than a thousand prostate tumours found the mismatch repair protein missing in about one in eighty, and twenty times more often in the highest-grade cancers.
A total of 1,133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing, and microsatellite instability was assessed by PCR and by mSINGS. Of the primary adenocarcinomas and small cell carcinomas together, 14 of 1,176, 1.2%, had MSH2 loss. Eight per cent of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9 to 10), 7 of 91, had MSH2 loss compared with 0.4%, 5 of 1,042, of tumours with any other score, and 2 of 43 small cell carcinomas, 5%. MSH2 loss was generally homogeneous, suggesting an early clonal event. Sequencing confirmed loss-of-function alterations in all 12 samples tested, with biallelic inactivation in 83% and hypermutation in 83%; 61% and 58% had definite microsatellite instability by PCR and mSINGS respectively, and 3 patients, 25%, had germline MSH2 mutations. Tumours with MSH2 loss had a higher density of infiltrating CD8-positive lymphocytes than grade-matched controls, 390 against 76 cells per square millimetre.
It gives a cheap way to find the rare men who could benefit from checkpoint blockade: an immunohistochemical stain on the highest-grade primary tumours, where the yield is twenty times higher than average. It also shows the loss is clonal and early, so the diagnostic block is an adequate place to look.
Shares MSH2, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome.
Shares MSH2, MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
Shares MSH2, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome.
Shares MSH2, dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Lynch syndrome.
Shares dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares MSH2, Lynch syndrome, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability.
Shares MSH2, Lynch syndrome, Mismatch repair & microsatellite instability, Germline vs somatic mutations.
Shares dMMR (mismatch repair deficiency by IHC), MSI-high (microsatellite instability by PCR or sequencing), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).