Categories: Neoplasm

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 164757 (gene) , 211980 (trait) , 114500 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: no

Mode of inheritance: Somatic mutation

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Species-specific name: Invasive transitional cell carcinoma of the bladder; Canine InvTCC; urothelial carcinomas; transitional cell carcinoma; TCC

Species-specific symbol: InvTCC

Mapping: Position 8296284 on chromosome CFA16 (Decker et al., 2015)

Markers: By genotyping biopsy samples or tissue from cytological slides taken from 87 dogs with prostate carcinomas (PCa), Grassinger et al. (2019) concluded that "BRAF mutation analysis is a highly specific method and may aid in confirming the diagnosis of PCa in histologically and cytologically questionable cases. PCa positive for BRAF mutation exhibited more criteria of malignancy than PCa without this mutation. The clinical, therapeutic, and prognostic relevance of these findings needs to be evaluated by further studies."

Molecular basis: Decker et al. (2015) reported that "four histologically confirmed canine InvTCC tumors [from] . . . two Scottish terriers, one West Highland white terrier and one Shetland sheepdog . . . harbor a nonsynonymous, single-nucleotide variant at genomic position 8296284 on Canis familiaris chromosome 16 (CFA16), which results in a valine to glutamic acid substitution at codon 595 of canine BRAF . . . . This mutation, BRAF(V595E), is homologous by multiple sequence alignment to the oncogenic human BRAF(V600E) mutation." IT IS IMPORTANT TO NOTE (as the authors stressed) THAT THIS IS A SOMATIC MUTATION, AND IS NOT INHERITED.

Thomas et al. (2023) "performed DNA sequencing analysis of 28 canine UC [urothelial carcinomas] cases that do not bear this mutation [BRAF(V595E), OMIA variant ID:93], to identify alternative mutations that may contribute to tumor development. We identified 13 specimens (46% of cases) harboring short in-frame deletions clustering elsewhere within the BRAF gene, or within MAP2K1, which also functions in the MAPK pathway."

Clinical features: Invasive transitional cell carcinoma usually manifests as a chronic urinary tract infection. The clinical signs are non-specific and include pollakiuria, haematuria, and stranguria commonly in association with other conditions such as urinary tract infection, bladder stones, benign polyps, and cystitis (Thomas et al., 2023). ITCC is usually diagnosed at an advanced stage (invasion of the detrusor muscle), where dogs may experience anuria (mass obstruction/urethral extension) (Thomas et al., 2023). Additionally, survival time can be less than 12 months from the time of diagnosis (Thomas et al., 2023). Gold standard for diagnosis is histopathologic evaluation of tissue biopsies (Thomas et al., 2023). Investigation of associated genes is possible (BRAF V595E + MAP2K1 ) from a urine sample with (droplet digital) PCR, however a negative result does not rule out ITCC (Thomas et al., 2023).

IT thanks DVM student Tori Stragliotto, who provided the basis of this contribution in May 2023.

Breeds: Beagle, Scottish Terrier, Shetland Sheepdog, West Highland White Terrier.

Associated genes: