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.
Highlights
Anal squamous cell carcinoma (ASCC) is a rare tumour that accounts for less than 5% of all lower gastrointestinal tract malignancies in Europe [1], but its incidence has increased in the last two decades, especially in HIV men [2, 3]
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 Anal squamous cell carcinomas (ASCC) such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%)
Genomic characterization of ASCC is crucial to better understand molecular mechanisms involved in anal carcinogenesis and identify new therapeutic targets and predictive biomarkers of response to chemoradiation
Summary
Anal squamous cell carcinoma (ASCC) is a rare tumour that accounts for less than 5% of all lower gastrointestinal tract malignancies in Europe [1], but its incidence has increased in the last two decades, especially in HIV men [2, 3]. Human papilloma virus (HPV) infection, predominantly by HPV-16, is the main risk factor of these tumours [4]. Other risk factors include anoreceptive intercourse, a high lifetime number of sexual partners, chronic immunosuppression and a history of smoking. A salvage abdominoperineal resection is indicated but 30 to 60% of operated patients will experience a locoregional and/or metastatic recurrence [6, 7]. In these patients with an inoperable locally advanced or metastatic disease, very few treatments are available and their effectiveness is limited. New therapeutic approaches and predictive factors of outcome are required in this context
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