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Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
Author(s) -
Temko Daniel,
Van Gool Inge C,
Rayner Emily,
Glaire Mark,
Makino Seiko,
Brown Matthew,
Chegwidden Laura,
Palles Claire,
Depreeuw Jeroen,
Beggs Andrew,
Stathopoulou Chaido,
Mason John,
Baker AnnMarie,
Williams Marc,
Cerundolo Vincenzo,
Rei Margarida,
Taylor Jenny C,
Schuh Anna,
Ahmed Ahmed,
Amant Frédéric,
Lambrechts Diether,
Smit Vincent THBM,
Bosse Tjalling,
Graham Trevor A,
Church David N,
Tomlinson Ian
Publication year - 2018
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5081
Subject(s) - genome instability , biology , carcinogenesis , somatic cell , germline mutation , mutation , cancer research , microsatellite instability , cancer , dna mismatch repair , exome sequencing , genetics , exonuclease , colorectal cancer , mutation rate , gene , dna damage , dna , allele , microsatellite , dna polymerase
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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.