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

Abstract

// Wulfran Cacheux 1, 2, *, # , Virginie Dangles-Marie 3, 4, *, # , Etienne Rouleau 2, * , Julien Lazartigues 2, * , Elodie Girard 5, * , Adrien Briaux 2, * , Pascale Mariani 6 , Sophie Richon 7 , Sophie Vacher 2 , Bruno Buecher 8 , Marion Richard-Molard 9 , Emmanuelle Jeannot 2 , Nicolas Servant 3 , Fereshteh Farkhondeh 10 , Odette Mariani 10 , Thomas Rio-Frio 11 , Sergio Roman-Roman 3 , Emmanuel Mitry 1 , Ivan Bieche 2, 12, * and Astrid Lièvre 1, 13, 14, * 1 Département d’oncologie médicale, Ensemble Hospitalier de l’Institut Curie, Hôpital René Huguenin, Saint-Cloud, 92210 Saint-Cloud, France 2 Département de Génétique, Unité de pharmacogénomique, Ensemble Hospitalier de l’Institut Curie, 75248 Paris Cedex 05, France 3 Département de Recherche Translationnelle, Centre de Recherche de l’Institut Curie, 75248 Paris Cedex 05, France 4 IFR71, Faculté des sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris, France 5 Plateforme de bioinfomatique, Centre de recherche de l’Institut Curie, 75248 Paris Cedex 05, INSERM, U900 Paris, France 6 Département de chirurgie oncologique, Ensemble Hospitalier de l’Institut Curie, 75248 Paris Cedex 05, France 7 Centre de recherche de l’Institut Curie, UMR144 Cell migration and invasion team, 75248 Paris Cedex 05, France 8 Département d’oncologie Médicale, Ensemble Hospitalier de l’Institut Curie, 75248 Paris Cedex 05, France 9 Département de radiothérapie, Ensemble Hospitalier de l’Institut Curie, Hôpital René Huguenin, 92210 Saint-Cloud, France 10 Département de Pathologie, Institut Curie, 75248 Paris Cedex 05, France 11 Institut Curie Genomics of Excellence (ICGex) Platform, Institut Curie, 75248 Paris Cedex 05, France 12 EA 7331, Faculté des sciences Pharmaceutiques et Biologiques, Université Paris Descartes, Sorbonne Paris Cité, 75270 Paris, France 13 Service des maladies de l’appareil digestif, Centre Hospitalier Universitaire de Rennes, 35033 Rennes Cedex 09, Université de Rennes 1, Faculté de Médecine, 35043 Rennes, France 14 Inserm ER440-Oncogenesis, Stress and Signaling, Rue Bataille Flandres-Dunkerque, 35042 Rennes, France * These authors contributed equally to this work # Co-first authors Correspondence to: Wulfran Cacheux, email: wulfran.cacheux@curie.fr Keywords: anal squamous cell carcinoma; whole exome sequencing; somatic mutation, copy number alteration; signalling pathway Received: August 13, 2017      Accepted: November 14, 2017      Published: December 08, 2017 ABSTRACT 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.