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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

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 n...

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Autores principales: 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, Ann‐Marie, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032922/
https://www.ncbi.nlm.nih.gov/pubmed/29604063
http://dx.doi.org/10.1002/path.5081
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author 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, Ann‐Marie
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
author_facet 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, Ann‐Marie
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
author_sort Temko, Daniel
collection PubMed
description 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.
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spelling pubmed-60329222018-07-12 Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response 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, Ann‐Marie 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 J Pathol Original Papers 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. John Wiley & Sons, Ltd 2018-04-30 2018-07 /pmc/articles/PMC6032922/ /pubmed/29604063 http://dx.doi.org/10.1002/path.5081 Text en © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Papers
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, Ann‐Marie
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
Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title_full Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title_fullStr Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title_full_unstemmed Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title_short Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
title_sort somatic pole exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response
topic Original Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032922/
https://www.ncbi.nlm.nih.gov/pubmed/29604063
http://dx.doi.org/10.1002/path.5081
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