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Pooling trials and cohorts covering 6,517 bowel cancers found that one in a hundred has a broken proofreading enzyme. Those tumours carry far more mutations than any other, attract as many immune cells as the mismatch repair deficient ones, and relapse far less often.
The association of POLE proofreading domain mutation with clinicopathological variables and immune response was examined in colorectal cancers from the VICTOR, QUASAR2 and PETACC-3 trials and eight cohorts, with prognosis in stage II and III disease assessed by Cox regression on pooled individual patient data from more than 4,500 cases. Pathogenic somatic POLE mutations were detected in 66 of 6,517 colorectal cancers (1.0%) and were mutually exclusive with mismatch repair deficiency (none of 66 against 833 of 6,211 determined for both). Compared with POLE wild-type cases, POLE-mutant patients were younger (median 54.5 against 67.2 years), more often male (75.8% against 55.5%), more often had right-sided tumours (68.8% against 39.8%) and were diagnosed at an earlier stage. POLE-mutant tumours displayed increased CD8-positive lymphocyte infiltration and expression of cytotoxic T-cell markers and effector cytokines, similar to mismatch repair deficient cancers. Both POLE mutation and mismatch repair deficiency were associated with reduced recurrence risk against mismatch repair proficient cancers (hazard ratios 0.34 and 0.72).
It defines a small group with an excellent prognosis that no repair immunohistochemistry panel or MSI assay will find, and it is the main argument for sequencing rather than staining alone in younger patients.
Shares POLE ultramutation (POLEmut), POLE, Oxford Cancer (Oxford University Hospitals and University of Oxford), DNA replication stress.
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), TMB-high (tumour mutational burden >= 10 mutations per megabase), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen, The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares Neoantigen, The cancer-immunity cycle, Tumour mutational burden (TMB), Whole-exome & whole-genome sequencing.
Shares Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR), Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Colorectal cancer.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Neoantigen, The cancer-immunity cycle, Colorectal cancer.
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB).
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, The Lancet, Colorectal cancer.