Identification of A Novel Papillomavirus Associated with Squamous Cell Carcinoma in A Domestic Cat

Abstract

Papillomaviruses infect the skin and mucosal surfaces of diverse animal hosts with consequences ranging from asymptomatic colonization to highly malignant epithelial cancers. Increasing evidence suggests a role for papillomaviruses in the most common cutaneous malignancy of domestic cats, squamous cell carcinoma (SCC). Using total DNA sequencing we identified a novel feline papillomavirus in a nasal biopsy taken from a cat presenting with both nasal cavity lymphoma and recurrent squamous cell carcinoma affecting the nasal planum. We designate this novel virus as Felis catus papillomavirus 6 (FcaPV6). The complete FcaPV6 7453 bp genome was similar to those of other feline papillomaviruses and phylogenetic analysis revealed that it was most closely related to FcaPV3, although was distinct enough to represent a new viral type. Classification of FcaPV6 in a new genus alongside FcaPVs 3, 4 and 5 is supported. Archived excisional biopsy of the SCC, taken 20 months prior to presentation, was intensely positive on p16 immunostaining. FcaPV6, amplified using virus-specific, but not consensus, PCR, was the only papillomavirus detected in DNA extracted from the SCC. Conversely, renal lymphoma, sampled at necropsy two months after presentation, tested negative on FcaPV6-specific PCR. In sum, using metagenomics we demonstrate the presence of a novel feline papillomavirus in association with cutaneous squamous cell carcinoma.

Keywords: cancer; cat; discovery; felid; feline; oncogenic; papillomavirus; pathogen; phylogeny; squamous cell carcinoma.

Figure 1

A recurrent invasive squamous cell carcinoma on the nasal planum (horizontal arrow) was adjacent the site of a biopsy (vertical arrow) from which high-grade lymphoma of the nasal cavity was diagnosed.

Figure 2

Felis catus Papillomavirus 6 (FcaPV6) genome configuration using metadata. The predicted ORFs are represented by the coloured inner segments. GC content is displayed in blue, percentage nucleotide polymorphism in orange and read coverage in yellow.

Figure 3

Evolutionary relationships of FcaPV6 to other mammalian papillomaviruses, including those previously identified in cats (Felis catus). Those papillomaviruses previously identified in cats are marked with animal symbols and in red, along with their respective genera. FcaPV6 is proposed to fall as part of a proposed new genus. All virus names contain their associated GenBank accession numbers. The tree is rooted using six nonmammalian papillomaviruses that have been removed to improve clarity. All horizontal branch lengths are scaled according to the number of amino acid substitutions per site, and the * denotes nodes with SH-like branch support values >0.95.

Figure 4

Photomicrograph of a nasal planum squamous cell carcinoma that contained FcaPV6 DNA. This biopsy was obtained 20 months prior to the SCC recurrence shown in Figure 1. Intense nuclear and cytoplasmic immunostaining using anti-p16^CDKN2A protein (p16) antibodies is visible diffusely within the neoplastic cells. There is minimal immunostaining within adjacent non-neoplastic epidermis (arrows). Hematoxylin counterstain.