OMIA:001512-9615 : Invasive transitional cell carcinoma in Canis lupus familiaris
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.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|BRAF||B-Raf proto-oncogene, serine/threonine kinase||Canis lupus familiaris||16||NC_051820.1 (8065738..8237942)||BRAF||Homologene, Ensembl , NCBI gene|
|MAP2K1||mitogen-activated protein kinase kinase 1||Canis lupus familiaris||30||NC_051834.1 (30879701..30957083)||MAP2K1||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|93||Invasive transitional cell carcinoma of the bladder||BRAF||missense||Naturally occurring variant||CanFam3.1||16||g.8296284T>A||c.1643T>A||p.(V548E)||XM_005629551.3; XP_005629608.1; published as somatic mutation p.(V594E)||2015||25767210|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2023||Thomas, R., Wiley, C.A., Droste, E.L., Robertson, J., Inman, B.A., Breen, M. :|
|Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption. PLoS Genet 19:e1010575, 2023. Pubmed reference: 37079639 . DOI: 10.1371/journal.pgen.1010575.|
|2022||Dhawan, D., Ramos-Vara, J.A., Utturkar, S.M., Ruple, A., Tersey, S.A., Nelson, J.B., Cooper, B.R., Heng, H.G., Ostrander, E.A., Parker, H.G., Hahn, N.M., Adams, L.G., Fulkerson, C.M., Childress, M.O., Bonney, P.L., Royce, C., Fourez, L.M., Enstrom, A.W., Ambrosius, L.A., Knapp, D.W. :|
|Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma. Front Oncol 12:1011969, 2022. Pubmed reference: 36439482 . DOI: 10.3389/fonc.2022.1011969.|
|Gedon, J., Kehl, A., Aupperle-Lellbach, H., von Bomhard, W., Schmidt, J.M. :|
|BRAF mutation status and its prognostic significance in 79 canine urothelial carcinomas: A retrospective study (2006-2019). Vet Comp Oncol 20:449-457, 2022. Pubmed reference: 34878687 . DOI: 10.1111/vco.12790.|
|2021||Rossman, P., Zabka, T.S., Ruple, A., Tuerck, D., Ramos-Vara, J.A., Liu, L., Mohallem, R., Merchant, M., Franco, J., Fulkerson, C.M., Bhide, K.P., Breen, M., Aryal, U.K., Murray, E., Dybdal, N., Utturkar, S.M., Fourez, L.M., Enstrom, A.W., Dhawan, D., Knapp, D.W. :|
|Phase I/II trial of vemurafenib in dogs with naturally occurring, BRAF-mutated urothelial carcinoma. Mol Cancer Ther 20:2177-2188, 2021. Pubmed reference: 34433660 . DOI: 10.1158/1535-7163.MCT-20-0893.|
|2019||Grassinger, J.M., Aupperle-Lellbach, H., Erhard, H., Merz, S., Klopfleisch, R. :|
|[Detection of BRAF mutation in canine prostatic diseases]. Tierarztl Prax Ausg K Kleintiere Heimtiere 47:313-320, 2019. Pubmed reference: 31627222 . DOI: 10.1055/a-0987-8212.|
|Knapp, D.W., Dhawan, D., Ramos-Vara, J.A., Ratliff, T.L., Cresswell, G.M., Utturkar, S., Sommer, B.C., Fulkerson, C.M., Hahn, N.M. :|
|Naturally-occurring invasive urothelial carcinoma in dogs, a unique model to drive advances in managing muscle invasive bladder cancer in humans. Front Oncol 9:1493, 2019. Pubmed reference: 32039002 . DOI: 10.3389/fonc.2019.01493.|
|2015||Decker, B., Parker, H.G., Dhawan, D., Kwon, E.M., Karlins, E., Davis, B.W., Ramos-Vara, J.A., Bonney, P.L., McNiel, E.A., Knapp, D.W., Ostrander, E.A. :|
|Homologous mutation to human BRAF V600E is common in naturally occurring canine bladder cancer--Evidence for a relevant model system and urine-based diagnostic test. Mol Cancer Res 13:993-1002, 2015. Pubmed reference: 25767210 . DOI: 10.1158/1541-7786.MCR-14-0689.|
|2014||Knapp, D.W., Ramos-Vara, J.A., Moore, G.E., Dhawan, D., Bonney, P.L., Young, K.E. :|
|Urinary bladder cancer in dogs, a naturally occurring model for cancer biology and drug development. ILAR J 55:100-18, 2014. Pubmed reference: 24936033 . DOI: 10.1093/ilar/ilu018.|
|2004||Glickman, LT., Raghavan, M., Knapp, DW., Bonney, PL., Dawson, MH. :|
|Herbicide exposure and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers. J Am Vet Med Assoc 224:1290-7, 2004. Pubmed reference: 15112777 .|
|2000||Knapp, D., Glickman, N., DeNicola, D., Bonney, P., Lin, T., Glickman, L. :|
|Naturally-occurring canine transitional cell carcinoma of the urinary bladder: A relevant model of human invasive bladder cancer Urology Oncology 5:47-59, 2000.|
|1989||Glickman, LT., Schofer, FS., McKee, LJ., Reif, JS., Goldschmidt, MH. :|
|Epidemiologic study of insecticide exposures, obesity, and risk of bladder cancer in household dogs. J Toxicol Environ Health 28:407-14, 1989. Pubmed reference: 2593174 . DOI: 10.1080/15287398909531360.|
|1976||Hayes, HM. :|
|Canine bladder cancer: epidemiologic features. Am J Epidemiol 104:673-7, 1976. Pubmed reference: 998613 .|
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