Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Daniel Temko, Inge C Van Gool, Emily Rayner, Mark Glaire, Seiko Makino, Matthew Brown, Laura Chegwidden, Claire Palles, Jeroen Depreeuw, Andrew Beggs, Chaido Stathopoulou, John Mason (+14 others)
2018 Journal of Pathology  
Conflicts of interest statement: All -none to declare. Running title: Somatic POLE mutations are early events in sporadic cancers Word count: Abstract: 223 words Manuscript (including Methods): 3966 words This article is ABSTRACT Genomic instability, a hallmark of cancer, is generally thought to occur in the mid to late stages of tumorigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease
more » ... n 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 POLEmutant cancers display the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumorigenesis. In POLE-mutant cancers, the proportion of monoclonal predicted neoantigens was similar to 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 an early, quite possibly initiating, event 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.
doi:10.1002/path.5081 pmid:29604063 pmcid:PMC6032922 fatcat:5ln5tbxhhzbj5dqbkz7fjwn4wi