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Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma

Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequenci...

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Autores principales: Cacheux, Wulfran, Dangles-Marie, Virginie, Rouleau, Etienne, Lazartigues, Julien, Girard, Elodie, Briaux, Adrien, Mariani, Pascale, Richon, Sophie, Vacher, Sophie, Buecher, Bruno, Richard-Molard, Marion, Jeannot, Emmanuelle, Servant, Nicolas, Farkhondeh, Fereshteh, Mariani, Odette, Rio-Frio, Thomas, Roman-Roman, Sergio, Mitry, Emmanuel, Bieche, Ivan, Lièvre, Astrid
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787481/
https://www.ncbi.nlm.nih.gov/pubmed/29416628
http://dx.doi.org/10.18632/oncotarget.23066
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author Cacheux, Wulfran
Dangles-Marie, Virginie
Rouleau, Etienne
Lazartigues, Julien
Girard, Elodie
Briaux, Adrien
Mariani, Pascale
Richon, Sophie
Vacher, Sophie
Buecher, Bruno
Richard-Molard, Marion
Jeannot, Emmanuelle
Servant, Nicolas
Farkhondeh, Fereshteh
Mariani, Odette
Rio-Frio, Thomas
Roman-Roman, Sergio
Mitry, Emmanuel
Bieche, Ivan
Lièvre, Astrid
author_facet Cacheux, Wulfran
Dangles-Marie, Virginie
Rouleau, Etienne
Lazartigues, Julien
Girard, Elodie
Briaux, Adrien
Mariani, Pascale
Richon, Sophie
Vacher, Sophie
Buecher, Bruno
Richard-Molard, Marion
Jeannot, Emmanuelle
Servant, Nicolas
Farkhondeh, Fereshteh
Mariani, Odette
Rio-Frio, Thomas
Roman-Roman, Sergio
Mitry, Emmanuel
Bieche, Ivan
Lièvre, Astrid
author_sort Cacheux, Wulfran
collection PubMed
description Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were PIK3CA (25%) followed by FBXW7 (15%), FAT1 (15%), and TRIP12 (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting PIK3CA) and losses of chromosome 11q (affecting ATM). The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy.
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spelling pubmed-57874812018-02-07 Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma Cacheux, Wulfran Dangles-Marie, Virginie Rouleau, Etienne Lazartigues, Julien Girard, Elodie Briaux, Adrien Mariani, Pascale Richon, Sophie Vacher, Sophie Buecher, Bruno Richard-Molard, Marion Jeannot, Emmanuelle Servant, Nicolas Farkhondeh, Fereshteh Mariani, Odette Rio-Frio, Thomas Roman-Roman, Sergio Mitry, Emmanuel Bieche, Ivan Lièvre, Astrid Oncotarget Research Paper Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were PIK3CA (25%) followed by FBXW7 (15%), FAT1 (15%), and TRIP12 (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting PIK3CA) and losses of chromosome 11q (affecting ATM). The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy. Impact Journals LLC 2017-12-08 /pmc/articles/PMC5787481/ /pubmed/29416628 http://dx.doi.org/10.18632/oncotarget.23066 Text en Copyright: © 2018 Cacheux et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Cacheux, Wulfran
Dangles-Marie, Virginie
Rouleau, Etienne
Lazartigues, Julien
Girard, Elodie
Briaux, Adrien
Mariani, Pascale
Richon, Sophie
Vacher, Sophie
Buecher, Bruno
Richard-Molard, Marion
Jeannot, Emmanuelle
Servant, Nicolas
Farkhondeh, Fereshteh
Mariani, Odette
Rio-Frio, Thomas
Roman-Roman, Sergio
Mitry, Emmanuel
Bieche, Ivan
Lièvre, Astrid
Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title_full Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title_fullStr Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title_full_unstemmed Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title_short Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
title_sort exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787481/
https://www.ncbi.nlm.nih.gov/pubmed/29416628
http://dx.doi.org/10.18632/oncotarget.23066
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