Journal
JOURNAL OF PATHOLOGY
Volume 245, Issue 3, Pages 283-296Publisher
WILEY
DOI: 10.1002/path.5081
Keywords
POLE; polymerase proofreading; mutation; endometrial cancer; colorectal cancer; precursor lesion
Funding
- NCI
- NIH
- Cancer Research UK [C6199/A10417, C399/A2291, C31641/A23923]
- European Union Seventh Framework Programme (FP7) [258236]
- European Research Council project EVOCAN
- Dutch Cancer Society
- Research Fund Flanders (F.W.O.) [G.0827.13]
- Medical Research Council
- Wellcome Trust
- Department of Health as part of a Health Innovation Challenge Fund [R6-388]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
- Ovarian Cancer Action
- EPSRC doctoral training grant via CoMPLEX
- Dutch Cancer Society Young Investigator Grant [10418]
- Wellcome Trust [102732/Z/13/Z, 090532/Z/09/Z]
- Medical Research Council [MR/M016587/1]
- Health Foundation/Academy of Medical Sciences Clinician Scientist Fellowship
- Wellcome Trust [102732/Z/13/Z] Funding Source: Wellcome Trust
- MRC [G0902418, MR/M016587/1, MR/M009157/1, MC_UU_00008/1] Funding Source: UKRI
- Medical Research Council [MR/M016587/1] Funding Source: researchfish
Ask authors/readers for more resources
Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non-malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE-mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE-mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8(+) T-cell infiltrate present in POLE-mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. (C) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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