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A pathogenic mutation in the proofreading part of the POLE gene gives an endometrial tumour hundreds of mutations per megabase and, paradoxically, one of the best outlooks of any womb cancer, so finding it can spare a woman chemotherapy or radiotherapy.
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.
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.
POLE and POLD1 are now on polyposis and colorectal germline panels, and the paper explains why a patient with many adenomas and an entirely normal mismatch repair panel still needs sequencing.
Shares Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, POLE, Advanced or recurrent endometrial cancer, Tumour mutational burden (TMB).
Shares Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer, Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Pembrolizumab.
Shares POLE, POLE-ultramutated endometrial cancer.
Shares Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP), POLE-ultramutated endometrial cancer, Uterine carcinosarcoma.
Shares Tumour mutational burden (TMB), Next-generation sequencing (NGS), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Colorectal cancer.
Shares No specific molecular profile (NSMP) endometrial cancer, Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP), POLE-ultramutated endometrial cancer, Uterine carcinosarcoma.
Shares Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP), POLE-ultramutated endometrial cancer, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares Endometrial cancer molecular classes (POLEmut, MMRd, p53abn, NSMP), Uterine carcinosarcoma.