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

Autor:	Temko D; Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Centre for Maths and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK.; Department of Computer Science, University College London, London, UK., Van Gool IC; Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands., Rayner E; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Glaire M; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Makino S; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Brown M; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Chegwidden L; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Palles C; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Depreeuw J; KU Leuven (University of Leuven), University Hospitals Leuven, Department of Obstetrics and Gynaecology, Division of Gynaecological Oncology, Leuven, Belgium.; KU Leuven, Department of Human Genetics, Laboratory for Translational Genetics, Leuven, Belgium.; VIB Centre for Cancer Biology, Laboratory for Translational Genetics, Leuven, Belgium., Beggs A; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Stathopoulou C; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Mason J; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Baker AM; Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Williams M; Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Department of Cell and Developmental Biology, University College London, London, UK., Cerundolo V; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Rei M; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK., Taylor JC; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Schuh A; Department of Oncology, University of Oxford, Oxford, UK., Ahmed A; Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.; Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford, UK., Amant F; Centre for Gynaecological Oncology Amsterdam, Netherlands Cancer Institute, Amsterdam, The Netherlands., Lambrechts D; KU Leuven, Department of Human Genetics, Laboratory for Translational Genetics, Leuven, Belgium.; VIB Centre for Cancer Biology, Laboratory for Translational Genetics, Leuven, Belgium., Smit VT; Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands., Bosse T; Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands., Graham TA; Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Church DN; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK., Tomlinson I; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
Jazyk:	angličtina
Zdroj:	The Journal of pathology [J Pathol] 2018 Jul; Vol. 245 (3), pp. 283-296. Date of Electronic Publication: 2018 Apr 30.
DOI:	10.1002/path.5081
Abstrakt:	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. (© 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)
Databáze:	MEDLINE
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