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

W. Cacheux (1) , V. Dangles-Marie (2, 3) , E. Rouleau (4) , J. Lazartigues (4) , E. Girard (5) , A. Briaux (4) , P. Mariani (4) , S. Richon (3, 6) , S. Vacher (4) , B. Buecher (4) , M. Richard-Molard (4) , E. Jeannot (4) , N. Servant (7) , F. Farkhondeh (4) , O. Mariani (4) , T. Rio-Frio (8) , S.R. Roman (7) , E. Mitry (4) , I. Bieche (9) , A. Lievre (4)

1 CRLCC René Huguenin
2 IFR71 - Institut des sciences du Médicament -Toxicologie - Chimie - Environnement
3 Centre de recherche de l'Institut Curie [Paris]
4 Institut Curie [Paris]
5 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
6 Morphogénèse et Signalisation Cellulaires
7 Département de Recherche Translationnelle
8 Plateforme de s
equenc
age ICGEX
9 EA 7331 - Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux

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.

Keywords: Somatic mutation; Whole exome sequencing; Signalling pathway; Anal squamous cell carcinoma; Copy number alteration

Domains: Life Sciences [q-bio]; Cancer

W. Cacheux, V. Dangles-Marie, E. Rouleau, J. Lazartigues, E. Girard, et al.. Exome sequencing reveals aberrant signalling pathways as hallmark of treatment-naive anal squamous cell carcinoma. Oncotarget, 2018, 9 (1), pp.464-476. ⟨10.18632/oncotarget.23066⟩. ⟨hal-01717339⟩