OMIA 000620-9615 : Histiocytosis, malignant in Canis lupus familiaris

In other species: pig , cattle

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: no

Year key variant first reported: 2017

Cross-species summary: This is a familial form of cancer. Also known as histiocytic sarcoma (HS)

History: The GWAS reported by Shearin et al. (2012) was "the first GWAS for histiocytic sarcoma in any species".

Inheritance: After examining the family data pertaining to 127 cases in Bermese mountain dogs, Padgett et al. (1995) concluded that the data were not consistent with any of the simple, single-locus models of inheritance. Considering it as a multifactorial disorder, they estimated the heritability of liability to be 0.298.

Mapping: The GWAS conducted with the Canine SNP20 Beadchip by Shearin et al. (2012) on affected and non-affected Bernese Mountain dogs from Europe and the USA identified a single region on chromosome CFA11. Fine-mapping and sequencing implicated "a single haplotype spanning MTAP and part of CDKN2A".

Asada et al. (2017) reported that "a 2-base (AT) insertion in exon 5 [of TP53], resulting in the introduction of a stop codon (c.446_447insAT, p.Tyr150SerfsX8)" is associated with histiocytic sarcoma in numerous breeds.

Genetic testing: A "pre-test", based on the results of Shearin et al. (2012) is available from Antagene:

Breeds: Bernese Mountain dog, Flat-coated retriever, Golden Retriever, Rottweiler.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
TP53 tumor protein p53 Canis lupus familiaris 5 NC_006587.3 (32565149..32561406) TP53 Homologene, Ensembl, NCBI gene


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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Histiocytosis, malignant TP53 insertion, small (<=20) 5 c.446_447insAT p.Tyr150SerfsX8 2017 28867679


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.
2017 Asada, H., Tsuboi, M., Chambers, J.K., Uchida, K., Tomiyasu, H., Goto-Koshino, Y., Ohno, K., Tsujimoto, H. :
A 2-base insertion in exon 5 is a common mutation of the TP53 gene in dogs with histiocytic sarcoma. J Vet Med Sci :, 2017. Pubmed reference: 28867679. DOI: 10.1292/jvms.17-0197.
2015 Heinrich, F., Contioso, V.B., Stein, V.M., Carlson, R., Tipold, A., Ulrich, R., Puff, C., Baumgärtner, W., Spitzbarth, I. :
Passage-dependent morphological and phenotypical changes of a canine histiocytic sarcoma cell line (DH82 cells). Vet Immunol Immunopathol 163:86-92, 2015. Pubmed reference: 25534080. DOI: 10.1016/j.vetimm.2014.11.006.
Mariani, C.L., Jennings, M.K., Olby, N.J., Borst, L.B., Brown, J.C., Robertson, I.D., Seiler, G.S., MacKillop, E. :
Histiocytic sarcoma with central nervous system involvement in dogs: 19 cases (2006-2012). J Vet Intern Med 29:607-13, 2015. Pubmed reference: 25711602. DOI: 10.1111/jvim.12554.
2014 Barrett, L.E., Pollard, R.E., Zwingenberger, A., Zierenberg-Ripoll, A., Skorupski, K.A. :
Radiographic characterization of primary lung tumors in 74 dogs. Vet Radiol Ultrasound 55:480-7, 2014. Pubmed reference: 24674604. DOI: 10.1111/vru.12154.
Boerkamp, K.M., van Steenbeek, F.G., Penning, L.C., Groot Koerkamp, M.J., van Leenen, D., Vos-Loohuis, M., Grinwis, G.C., Rutteman, G.R. :
The two main forms of histiocytic sarcoma in the predisposed Flatcoated retriever dog display variation in gene expression. PLoS One 9:e98258, 2014. Pubmed reference: 24886914. DOI: 10.1371/journal.pone.0098258.
Chikazawa, S., Kitahara, Y., Ando, E., Hori, Y., Hoshi, F., Kanai, K., Ito, N., Higuchi, S. :
Erythrophagocytosis enhances heme-dependent cytotoxicity of antimalarial drugs in canine histiocytic sarcoma cell line DH82. J Vet Med Sci 76:249-53, 2014. Pubmed reference: 24065080.
Davis, B.W., Ostrander, E.A. :
Domestic dogs and cancer research: a breed-based genomics approach. ILAR J 55:59-68, 2014. Pubmed reference: 24936030. DOI: 10.1093/ilar/ilu017.
Denstedt, E. :
Suspected disseminated histiocytic sarcoma in a 3-year-old Perro de Presa Canario dog. Can Vet J 55:181-4, 2014. Pubmed reference: 24489399.
Empl, M.T., Macke, S., Winterhalter, P., Puff, C., Lapp, S., Stoica, G., Baumgärtner, W., Steinberg, P. :
The growth of the canine glioblastoma cell line D-GBM and the canine histiocytic sarcoma cell line DH82 is inhibited by the resveratrol oligomers hopeaphenol and r2-viniferin. Vet Comp Oncol 12:149-59, 2014. Pubmed reference: 22882564. DOI: 10.1111/j.1476-5829.2012.00349.x.
Moore, P.F. :
A review of histiocytic diseases of dogs and cats. Vet Pathol 51:167-84, 2014. Pubmed reference: 24395976. DOI: 10.1177/0300985813510413.
Takahashi, M., Tomiyasu, H., Hotta, E., Asada, H., Fukushima, K., Kanemoto, H., Fujino, Y., Ohno, K., Uchida, K., Nakayama, H., Tsujimoto, H. :
Clinical characteristics and prognostic factors in dogs with histiocytic sarcomas in Japan. J Vet Med Sci 76:661-6, 2014. Pubmed reference: 24441652.
VanderHart, D.J., Reese, D.J., Greenberg, S.M. :
What is your diagnosis? Histiocytic sarcoma. J Am Vet Med Assoc 244:899-901, 2014. Pubmed reference: 24697763. DOI: 10.2460/javma.244.8.899.
2013 Boerkamp, K.M., van der Kooij, M., van Steenbeek, F.G., van Wolferen, M.E., Groot Koerkamp, M.J., van Leenen, D., Grinwis, G.C., Penning, L.C., Wiemer, E.A., Rutteman, G.R. :
Gene expression profiling of histiocytic sarcomas in a canine model: the predisposed flatcoated retriever dog. PLoS One 8:e71094, 2013. Pubmed reference: 23936488. DOI: 10.1371/journal.pone.0071094.
Dobson, J.M. :
Breed-predispositions to cancer in pedigree dogs. ISRN Vet Sci 2013:941275, 2013. Pubmed reference: 23738139. DOI: 10.1155/2013/941275.
Erich, S.A., Rutteman, G.R., Teske, E. :
Causes of death and the impact of histiocytic sarcoma on the life expectancy of the Dutch population of Bernese mountain dogs and Flat-coated retrievers. Vet J 198:678-83, 2013. Pubmed reference: 24231621. DOI: 10.1016/j.tvjl.2013.09.062.
Ito, K., Kuroki, S., Kobayashi, M., Ono, K., Washizu, T., Bonkobara, M. :
Identification of dasatinib as an in vitro potent growth inhibitor of canine histiocytic sarcoma cells. Vet J 196:536-40, 2013. Pubmed reference: 23369384. DOI: 10.1016/j.tvjl.2012.12.016.
Nikolic Nielsen, L., Kjelgaard-Hansen, M., Kristensen, A.T. :
Monocyte chemotactic protein-1 and other inflammatory parameters in Bernese Mountain dogs with disseminated histiocytic sarcoma. Vet J 198:424-8, 2013. Pubmed reference: 23992872. DOI: 10.1016/j.tvjl.2013.07.030.
Silva, G., Fachin, A.L., Beleboni, R.O., França, S.C., Marins, M. :
In vitro action of flavonoids in the canine malignant histiocytic cell line DH82. Molecules 18:15448-63, 2013. Pubmed reference: 24352006. DOI: 10.3390/molecules181215448.
Thakkar, P., Pease, A.P., Guiot, L.P., Fitzgerald, S.D., Adu Addai, B., Smedley, R.C. :
What is your diagnosis? Disseminated histiocytic sarcoma. J Am Vet Med Assoc 243:1255-7, 2013. Pubmed reference: 24134574. DOI: 10.2460/javma.243.9.1255.
Yamazaki, H., Takagi, S., Hoshino, Y., Hosoya, K., Okumura, M. :
Inhibition of survivin influences the biological activities of canine histiocytic sarcoma cell lines. PLoS One 8:e79810, 2013. Pubmed reference: 24260303. DOI: 10.1371/journal.pone.0079810.
Yamazaki, H., Takagi, S., Oh, N., Hoshino, Y., Hosoya, K., Okumura, M. :
Comparative analysis of mRNA expression of surface antigens between histiocytic and nonhistiocytic sarcoma in dogs. J Vet Intern Med 28:204-10, 2013. Pubmed reference: 24428323. DOI: 10.1111/jvim.12244.
van Kuijk, L., van Ginkel, K., de Vos, J.P., Brearley, M.J., Butinar, J., Gielen, I., van Garderen, E., Chiers, K., Verhoeven, P.S. :
Peri-articular histiocytic sarcoma and previous joint disease in Bernese Mountain Dogs. J Vet Intern Med 27:293-9, 2013. Pubmed reference: 23458888. DOI: 10.1111/jvim.12059.
2012 Arnold, E.J., Pressler, B.M., Heng, H.G. :
What is your diagnosis? Histiocytic sarcoma. J Am Vet Med Assoc 240:821-3, 2012. Pubmed reference: 22443434. DOI: 10.2460/javma.240.7.821.
Hafeman, S.D., Varland, D., Dow, S.W. :
Bisphosphonates significantly increase the activity of doxorubicin or vincristine against canine malignant histiocytosis cells. Vet Comp Oncol 10:44-56, 2012. Pubmed reference: 22236140. DOI: 10.1111/j.1476-5829.2011.00274.x.
Mastrorilli, C., Spangler, E.A., Christopherson, P.W., Aubry, O.A., Newton, J.C., Smith, A.N., Kennis, R.A., Weismann, J.L., Moore, P.F. :
Multifocal cutaneous histiocytic sarcoma in a young dog and review of histiocytic cell immunophenotyping. Vet Clin Pathol 41:412-8, 2012. Pubmed reference: 22747712. DOI: 10.1111/j.1939-165X.2012.00449.x.
Nielsen, L.N., McEvoy, F., Jessen, L.R., Kristensen, A.T. :
Investigation of a screening programme and the possible identification of biomarkers for early disseminated histiocytic sarcoma in Bernese Mountain dogs. Vet Comp Oncol 10:124-34, 2012. Pubmed reference: 22235831. DOI: 10.1111/j.1476-5829.2011.00285.x.
Sapierzyński, R., Jagielski, D., Dolka, I., Fabisiak, M. :
Cytopathological diagnosis of visceral histiocytic sarcoma in five dogs. Pol J Vet Sci 15:751-8, 2012. Pubmed reference: 23390766.
Shearin, A.L., Hedan, B., Cadieu, E., Erich, S.A., Schmidt, E.V., Faden, D.L., Cullen, J., Abadie, J., Kwon, E.M., Gröne, A., Devauchelle, P., Rimbault, M., Karyadi, D.M., Lynch, M., Galibert, F., Breen, M., Rutteman, G.R., André, C., Parker, H.G., Ostrander, E.A. :
The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer. Cancer Epidemiol Biomarkers Prev 21:1019-27, 2012. Pubmed reference: 22623710. DOI: 10.1158/1055-9965.EPI-12-0190-T.
Tsai, P.C., Breen, M. :
Array-based comparative genomic hybridization-guided identification of reference genes for normalization of real-time quantitative polymerase chain reaction assay data for lymphomas, histiocytic sarcomas, and osteosarcomas of dogs. Am J Vet Res 73:1335-43, 2012. Pubmed reference: 22924713. DOI: 10.2460/ajvr.73.9.1335.
Tsai, S., Sutherland-Smith, J., Burgess, K., Ruthazer, R., Sato, A. :
Imaging characteristics of intrathoracic histiocytic sarcoma in dogs. Vet Radiol Ultrasound 53:21-7, 2012. Pubmed reference: 21831241. DOI: 10.1111/j.1740-8261.2011.01863.x.
2011 Constantino-Casas, F., Mayhew, D., Hoather, T.M., Dobson, J.M. :
The clinical presentation and histopathologic-immunohistochemical classification of histiocytic sarcomas in the Flat Coated Retriever. Vet Pathol 48:764-71, 2011. Pubmed reference: 20930108. DOI: 10.1177/0300985810385153.
Hedan, B., Thomas, R., Motsinger-Reif, A., Abadie, J., Andre, C., Cullen, J., Breen, M. :
Molecular cytogenetic characterization of canine histiocytic sarcoma: A spontaneous model for human histiocytic cancer identifies deletion of tumor suppressor genes and highlights influence of genetic background on tumor behavior. BMC Cancer 11:201, 2011. Pubmed reference: 21615919. DOI: 10.1186/1471-2407-11-201.
Klahn, S.L., Kitchell, B.E., Dervisis, N.G. :
Evaluation and comparison of outcomes in dogs with periarticular and nonperiarticular histiocytic sarcoma. J Am Vet Med Assoc 239:90-6, 2011. Pubmed reference: 21718201. DOI: 10.2460/javma.239.1.90.
Soare, T., Noble, P.J., Hetzel, U., Fonfara, S., Kipar, A. :
Paraneoplastic syndrome in haemophagocytic histiocytic sarcoma in a dog. J Comp Pathol 146:168-74, 2011. Pubmed reference: 21741052. DOI: 10.1016/j.jcpa.2011.05.006.
Sterenczak, K.A., Kleinschmidt, S., Wefstaedt, P., Eberle, N., Hewicker-Trautwein, M., Bullerdiek, J., Nolte, I., Murua Escobar, H. :
Quantitative PCR and immunohistochemical analyses of HMGB1 and RAGE expression in canine disseminated histiocytic sarcoma (malignant histiocytosis). Anticancer Res 31:1541-8, 2011. Pubmed reference: 21617208.
2010 André, C., Abadie, J., Hedan, B., de Brito, C., Lagadic, M., Poujade, A., Devauchelle, P. :
Proliférations histiocytaires canines. D’après une étude épidémiologique, clinique et génétique de 100 cas de sarcome histiocytaire chez le Bouvier bernois. [Canine histiocytic proliferations. From an epidemiological, clinical, and genetic study of 100 histiocytic sarcomas in the Bernese mountain dog breed] Pratique médicale et chirurgicale de l’animal de compagnie (PMAC) 45:9-17, 2010.
Castellanos, V.C., O'Neill, S., Seiler, G.S. :
What is your diagnosis? Histiocytic sarcoma. J Am Vet Med Assoc 236:1293-4, 2010. Pubmed reference: 20550442. DOI: 10.2460/javma.236.12.1293.
Friedrichs, K.R., Thomas, C., Plier, M., Andrews, G.A., Chavey, P.S., Young, K.M. :
Evaluation of serum ferritin as a tumor marker for canine histiocytic sarcoma. J Vet Intern Med 24:904-11, 2010. Pubmed reference: 20561186. DOI: 10.1111/j.1939-1676.2010.0543.x.
Hafeman, S., London, C., Elmslie, R., Dow, S. :
Evaluation of liposomal clodronate for treatment of malignant histiocytosis in dogs. Cancer Immunol Immunother 59:441-52, 2010. Pubmed reference: 19760220. DOI: 10.1007/s00262-009-0763-y.
Nielsen, L., Andreasen, SN., Andersen, SD., Kristensen, AT. :
Malignant histiocytosis and other causes of death in Bernese mountain dogs in Denmark. Vet Rec 166:199-202, 2010. Pubmed reference: 20154310. DOI: 10.1136/vr.b4756.
Rassnick, K.M., Moore, A.S., Russell, D.S., Northrup, N.C., Kristal, O., Bailey, D.B., Flory, A.B., Kiselow, M.A., Intile, J.L. :
Phase II, open-label trial of single-agent CCNU in dogs with previously untreated histiocytic sarcoma. J Vet Intern Med 24:1528-31, 2010. Pubmed reference: 21155191.
2009 Abadie, J., Hédan, B., Cadieu, E., De Brito, C., Devauchelle, P., Bourgain, C., Parker, H.G., Vaysse, A., Margaritte-Jeannin, P., Galibert, F., Ostrander, E.A., André, C. :
Epidemiology, pathology, and genetics of histiocytic sarcoma in the Bernese mountain dog breed. J Hered 100 Suppl 1:S19-27, 2009. Pubmed reference: 19531730. DOI: 10.1093/jhered/esp039.
Maruo, T., Namikawa, K., Kunihiro, A., Lynch, J., Shida, T., Kishikawa, S. :
Large granular lymphocytic leukaemia complicated with histiocytic sarcoma in a dog. J S Afr Vet Assoc 80:261-3, 2009. Pubmed reference: 20458870.
Wagter, H.W., Vos, A.J., van den Ingh, T. :
[A localised histocytic sarcoma in the stomach of a dog]. Tijdschr Diergeneeskd 134:526-8, 2009. Pubmed reference: 19579381.
2008 Coleman, K.D., Lurie, D.M., Blaik, M.A., Demuth, G., Kirkby, K. :
What is your diagnosis? Histiocytic sarcoma. J Am Vet Med Assoc 232:1801-2, 2008. Pubmed reference: 18598147. DOI: 10.2460/javma.232.12.1801.
2007 Fulmer, A.K., Mauldin, G.E. :
Canine histiocytic neoplasia: an overview. Can Vet J 48:1041-3, 1046-50, 2007. Pubmed reference: 17987966.
Schultz, R.M., Puchalski, S.M., Kent, M., Moore, P.F. :
Skeletal lesions of histiocytic sarcoma in nineteen dogs. Vet Radiol Ultrasound 48:539-43, 2007. Pubmed reference: 18018725.
2006 Dobson, J., Villiers, E., Roulois, A., Gould, S., Mellor, P., Hoather, T., Watson, P. :
Histiocytic sarcoma of the spleen in flat-coated retrievers with regenerative anaemia and hypoproteinaemia. Vet Rec 158:825-9, 2006. Pubmed reference: 16782856.
Soller, J.T., Murua Escobar, H., Janssen, M., Fork, M., Bullerdiek, J., Nolte, I. :
Cytokine genes single nucleotide polymorphism (SNP) screening analyses in canine malignant histiocytosis. Anticancer Res 26:3417-20, 2006. Pubmed reference: 17094461.
Thio, T., Hilbe, M., Grest, P., Pospischil, A. :
Malignant histiocytosis of the brain in three dogs. J Comp Pathol 134:241-4, 2006. Pubmed reference: 16537081. DOI: 10.1016/j.jcpa.2005.09.005.
Voegeli, E., Welle, M., Hauser, B., Dolf, G., Flückiger, M. :
[Histiocytic sarcoma in the Swiss population of Bernese mountain dogs: a retrospective study of its genetic predisposition]. Schweiz Arch Tierheilkd 148:281-8, 2006. Pubmed reference: 16826705. DOI: 10.1024/0036-7281.148.6.281.
Zavodovskaya, R., Liao, AT., Jones, CL., Yip, B., Chien, MB., Moore, PF., London, CA. :
Evaluation of dysregulation of the receptor tyrosine kinases Kit, Flt3, and Met in histiocytic sarcomas of dogs. Am J Vet Res 67:633-41, 2006. Pubmed reference: 16579756. DOI: 10.2460/ajvr.67.4.633.
1996 Ramsey, I.K., Mckay, J.S., Rudorf, H., Dobson, J.M. :
Malignant histiocytosis in three Bernese Mountain dogs Veterinary Record 138:440-444, 1996. Pubmed reference: 8735262.
1995 Padgett, G.A., Madewell, B.R., Keller, E.T., Todar, L., Packard, M. :
Inheritance of histiocytosis in Bernese mountain dogs Journal of Small Animal Practice 36:93-98, 1995. Pubmed reference: 7783441.
Paterson, S., Boydell, P., Pike, R. :
Systemic histiocytosis in the Bernese mountain dog Journal of Small Animal Practice 36:233-236, 1995. Pubmed reference: 7650919.
1993 Hayden, D.W., Waters, D.J., Burke, B.A., Manivel, J.C. :
Disseminated Malignant Histiocytosis in a Golden Retriever - Clinicopathologic, Ultrastructural, and Immunohistochemical Findings Veterinary Pathology 30:256-264, 1993. Pubmed reference: 8333107.

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