# Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer

Source: https://onco.cc/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/  
OnCo record `paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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).

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Lancet Gastroenterology and Hepatology
- Year: 2016
- DOI: 10.1016/S2468-1253(16)30014-0
- Authors: Domingo E, Freeman-Mills L, Rayner E, et al.
- Findings: Pathogenic somatic POLE mutation in 66 of 6,517 colorectal cancers (1.0%), mutually exclusive with mismatch repair deficiency.; POLE-mutant patients younger (median 54.5 years) and more often male.; Recurrence hazard ratio 0.34 against mismatch repair proficient disease, with CD8 infiltration matching deficient tumours.
- What it means: 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.
- Caveats: Retrospective and pooled, with varied POLE calling methods.; Only 66 cases, so the prognostic estimate is wide.; Checkpoint inhibitors were not used; the immunotherapy case in POLE-mutant colorectal cancer rests on case series.

## Sources

- Domingo et al., Lancet Gastroenterol Hepatol 2016: somatic POLE proofreading mutation, immune response and prognosis in 6,517 colorectal cancers: https://doi.org/10.1016/S2468-1253(16)30014-0
- PubMed: https://pubmed.ncbi.nlm.nih.gov/28404093/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [Tumour mutational burden testing](https://onco.cc/technologies/tmb-testing/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [POLE](https://onco.cc/targets/pole/)
- institutions: [Oxford Cancer (Oxford University Hospitals and University of Oxford)](https://onco.cc/institutions/oxford-cancer/)
- pathways: [DNA replication stress](https://onco.cc/pathways/replication-stress/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [The cancer-immunity cycle](https://onco.cc/pathways/cancer-immunity-cycle/)
- terms: [Microsatellite-stable (MSS) / mismatch-repair proficient (pMMR)](https://onco.cc/terms/mss-pmmr/), [Neoantigen](https://onco.cc/terms/neoantigen/), [POLE ultramutation (POLEmut)](https://onco.cc/terms/pole-ultramutation/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- journals: [The Lancet](https://onco.cc/journals/lancet/)
- biomarkers: [TMB-high (tumour mutational burden >= 10 mutations per megabase)](https://onco.cc/biomarkers/tmb-high/)

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