Morphological, immunophenotypical and molecular features of hypermutation in colorectal carcinomas with mutations in DNA polymerase ε (POLE)

Aims Colorectal carcinomas (CRC) with mismatch repair (MMR) deficiency have increased tumour mutation burden and respond to immune check‐point inhibitor therapy. The Cancer Genome Atlas identified hypermutated CRCs with somatic mutations in DNA polymerase ε ( POLE ) with mutation burdens exceeding that of MMR‐deficient CRCs. Methods and results To identify the morphological, immunophenotypical and molecular features of POLE ‐mutated CRCs, 63 consecutive MMR‐intact CRCs were evaluated by Sanger sequencing for POLE exonuclease domain mutations in exons 9, 11, 13 and 14 and confirmed by next‐generation sequencing. Tumour immune microenvironment and IMMUNOSCORE® 1 were assessed in POLE ‐mutated CRCs using immunohistochemistry to detect CD3 + /CD8 + tumour‐infiltrating lymphocytes and compared to 59 non‐ POLE mutated MMR‐intact CRC, 10 non‐ POLE mutated MMR‐deficient CRCs and 223 normal colonic mucosa. Conclusions A total of 4.8% CRC (four MMR‐intact primary and one MMR‐intact metastasis) harboured POLE mutations in amino acid 286 in exon 9 (p.P286R) or exon 13 (p.V411L). POLE ‐mutated CRCs arose in the transverse colon and rectum, were male‐predominant, younger and showed increased tumour‐infiltrating lymphocytes and immune cells at the tumour–stromal interface. The patient with metastatic POLE ‐mutated CRC was placed on PD‐1 inhibitor treatment with marked and sustained response. These data indicate that POLE ‐mutated CRCs have hypermutated phenotypes despite MMR‐intact status, with mutation burdens higher than that in microsatellite‐unstable CRCs. Given the recent approval for treatment of microsatellite‐unstable cancer with immune check‐point inhibitors, assessment of POLE status may help to guide therapeutic decisions for hypermutated tumours with intact MMR that would otherwise be missed by routine testing.