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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Published in:Oncotarget 2018-01, Vol.9 (1), p.464-476
Main Authors: 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
Format: Article
Language:English
Subjects:
Cancer
Life Sciences
Research Paper
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Summary: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 (25%) followed by (15%), (15%) and (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting ) and losses of chromosome 11q (affecting . 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.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.23066