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Feline oral squamous cell carcinoma (FOSCC) and human head and neck squamous cell carcinoma (HNSCC) are the 4th most common malignant neoplasms in cats and humans. Most cats are not treated due to the poor prognosis and die of their disease within a few months of diagnosis. In humans, despite surgery, radiation therapy, and chemotherapy, 1/3 of patients develop loco-regional recurrence within 5 years. FOSCC has commonly been proposed as a model for HNSCC since FOSCC is a spontaneous model and exhibits similar biologic behaviour, treatment course, and outcome to the human disease. The objective of this study was to identify genetic similarities and differences with HNSCC, therapeutic targets, and possible causes of FOSCC through whole exome sequencing. Thirty-six matched normal FOSCC tumours and three matched normal chronic gingivostomatitis lesions were sequenced with a previously validated custom Roche Nimblegen exome reagent, based on the Felis_catus_9.0 genome assembly, covering 35.7 Mb. The exome libraries were pooled and sequenced on the Illumina Novaseq6000 as 2 × 150 bp reads. The data was analysed with the McDonnell Genome Institute's (MGI) cancer informatics pipelines, namely the Genome Modelling System (GMS), which was adapted to the feline genome. TP53 harboured consequential variants in 71% of the FOSCC tumours and was the most commonly mutated gene. Consequential variants in TTN were seen in 18% tumours and consequential variants in FSIP2, LRP1B, RYR2 were seen 9% of tumours. Genes with highly recurrent copy number variants (CNVs) included CKDN2A, PTEN, and MYC. TMB was very low, 0-1.6 (mean 0.66). Six cats had a history of chronic gingivostomatitis for years before the diagnosis of FOSCC. Despite the low TMB, the genomic landscape of FOSCC parallels HPV-negative HNSCC. Aside from TP53, recurrent small-scale mutations in FOSCC were uncommon, but recurrent CNVs were common. FOSCC is a genetically and clinically heterogenous cancer. A multifactorial cause is suspected. Chronic gingivostomatitis, immunosuppression, and/or viral infection may be associated with FOSCC in young cats.