POLE ultramutation (POLEmut)

What is measured: a pathogenic mutation in the exonuclease (proofreading) domain of DNA polymerase epsilon, at hotspots such as P286R, V411L, S297F, A456P and S459F. How: targeted sequencing of tumour DNA; it is the first step of the ProMisE and WHO 2020 molecular classification and is read before p53 and mismatch repair immunohistochemistry because a POLE mutation trumps an abnormal p53 or a mismatch repair loss found alongside it. About 7 to 8 percent of endometrial carcinomas, mostly early stage and often high grade under the microscope yet with near-zero recurrence: the PORTEC-3 molecular analysis found almost no relapses in the POLEmut group whichever adjuvant treatment was given. The tumours are ultramutated (over 100 mutations per megabase), heavily infiltrated by lymphocytes, and respond to immune checkpoint inhibitors in the rare advanced case. What a positive result changes: de-escalation, tested in PORTEC-4a and the RAINBO POLEmut-BLUE trial, where stage I to II POLEmut cancers receive no adjuvant therapy; non-pathogenic POLE variants outside the domain do not count. Where it matters: the POLE-ultramutated endometrial page, advanced and recurrent endometrial cancer, uterine carcinosarcoma (rare, favourable); also rare colorectal and glial tumours.