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BMC Veterinary Research Oct 2020The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost in a variety of solid and hematopoietic malignancies in humans. Dysregulation of...
BACKGROUND
The WW domain-containing oxidoreductase (WWOX) tumor suppressor gene is frequently lost in a variety of solid and hematopoietic malignancies in humans. Dysregulation of WWOX has been implicated as playing a key role in tumor cell survival, DNA damage repair, and genomic stability. The purpose of this study was to characterize WWOX expression in spontaneous canine mast cell tumors (MCTs) and malignant cell lines and investigate the potential contribution of WWOX loss on malignant mast cell behavior.
METHODS/RESULTS
WWOX expression is decreased in primary canine MCTs and malignant mast cell lines compared to normal canine bone marrow-cultured mast cells. In transformed canine mastocytoma cell lines, overexpression of WWOX or WWOX knockdown had no effect on mast cell viability. Inhibition of WWOX enhanced clonogenic survival following treatment with ionizing radiation in the C2 mast cell line. Lastly, immunohistochemistry for WWOX was performed using a canine MCT tissue microarray, demonstrating that WWOX staining intensity and percent of cells staining for WWOX is decreased in high-grade MCTs compared to low-grade MCTs.
CONCLUSIONS
These data suggest that WWOX expression is attenuated or lost in primary canine MCTs and malignant mast cell lines. Given the observed increase in clonogenic survival in WWOX-deficient C2 mast cells treated with ionizing radiation, further investigation of WWOX and its role in mediating the DNA damage response in malignant mast cells is warranted.
Topics: Animals; Cell Line, Tumor; Dogs; Gene Expression Regulation, Neoplastic; Mast Cells; Mastocytoma; Skin Neoplasms; Tumor Suppressor Proteins; WW Domain-Containing Oxidoreductase
PubMed: 33129329
DOI: 10.1186/s12917-020-02638-3 -
Journal of Cutaneous Pathology Nov 2021We present a case of an adult male with a solitary mast cell tumor of the skin with unusual nuclear pleomorphism and mitotic activity. The tumor was excised, recurred...
We present a case of an adult male with a solitary mast cell tumor of the skin with unusual nuclear pleomorphism and mitotic activity. The tumor was excised, recurred within 2 years, was reexcised after 4 years and did not recur >6 years after diagnosis. The tumor showed progressive cytonuclear atypia and a high mitotic and proliferation rate by Ki67-staining from the onset. No KIT mutations were identified in the tumor and bone marrow. Serum tryptase levels and a bone marrow aspirate and trephine biopsy were normal. Although the histomorphology of the skin tumor was consistent with mast cell sarcoma, the clinical behavior without systemic progression argued against this diagnosis. The tumor was finally considered as atypical mastocytoma, borderline to mast cell sarcoma. Currently, the patient is in close follow-up and still in complete remission.
Topics: Adult; Diagnosis, Differential; Humans; Male; Mast-Cell Sarcoma; Mastocytoma, Skin
PubMed: 34152029
DOI: 10.1111/cup.14088 -
The Pan African Medical Journal 2019Isolated mastocytoma is the most common form of mastocytosis in children. Prognosis is good, as in all other forms of mastocytosis in children, with possibility of...
Isolated mastocytoma is the most common form of mastocytosis in children. Prognosis is good, as in all other forms of mastocytosis in children, with possibility of spontaneous regression. Dermocorticoids can accelerate this regression, as it is the case for our patient.
Topics: Adrenal Cortex Hormones; Humans; Infant; Male; Mastocytoma, Skin; Prognosis
PubMed: 31143350
DOI: 10.11604/pamj.2019.32.45.14356 -
Journal of Veterinary Diagnostic... Sep 2019DNA amplification by PCR detects exon 11 internal tandem duplications in canine mast cell tumors (MCTs). Tissue-specific inhibitors often contaminate DNA extracted from...
DNA amplification by PCR detects exon 11 internal tandem duplications in canine mast cell tumors (MCTs). Tissue-specific inhibitors often contaminate DNA extracted from formalin-fixed, paraffin-embedded (FFPE) canine MCTs, blocking PCR amplification and, consequently, preventing mutation detection. We used a commercial kit to extract DNA from FFPE canine MCTs. Two independent PCR assays, each with one primer set, were used to amplify target genes ( and ) directly after FFPE DNA extraction. PCR amplification failed with at least one primer set in 153 of 280 samples (54.6%, 95% CI: 48.8-60.5%). One or 2 DNA washing steps were required to remove PCR inhibitors in 130 of 280 (46.4%) and 23 of 280 (8.2%) of these cases, respectively. DNA concentration and quality (A/A and A/A) either pre- or post-washing were not associated with ability of the samples to be amplified by PCR using both and primer sets. Low-grade and subcutaneous MCTs were less likely to amplify directly after DNA extraction and without any washing steps compared to high-grade MCTs using gene primers.
Topics: Animals; Circulating Tumor DNA; Dog Diseases; Dogs; Formaldehyde; Mast Cells; Mastocytoma; Mutation; Nucleic Acid Amplification Techniques; Paraffin Embedding; Polymerase Chain Reaction; Proto-Oncogene Proteins c-kit; Skin Neoplasms
PubMed: 31378162
DOI: 10.1177/1040638719867743 -
The Canadian Veterinary Journal = La... Aug 2015Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are...
Intravenous paclitaxel has been underused in dogs due to severe and acute hypersensitivity reactions. Subcutaneous (SC) administration of paclitaxel and its safety are unknown. In this preliminary study, SC administration of paclitaxel was evaluated for hypersensitivity reactions and toxicity in 21 dogs with advanced cancer. Dogs received 1 to 5 paclitaxel doses, ranging from 85 to 170 mg/m(2), SC every 14 or 21 days. A total of 40 paclitaxel doses were administered and none of the 21 dogs developed systemic or acute local hypersensitivity reactions. Severe skin lesions at the injection site developed in 2 dogs after the 4th injection at the same location. Grade 4 neutropenia was observed in 50% of the dogs 5 days after the first treatment at 115 mg/m(2) (n = 14). Two animals developed Grade 5 diarrhea and died likely due to hemodynamic failure or sepsis. Paclitaxel can be administered SC in dogs with no hypersensitivity reaction.
Topics: Animals; Carcinoma; Dog Diseases; Dogs; Female; Injections, Subcutaneous; Lymphoma; Male; Mastocytoma; Paclitaxel; Sarcoma
PubMed: 26246628
DOI: No ID Found -
Indian Journal of Dermatology Nov 2014A 50-day-old female child presented with asymptomatic skin colored raised lesion on the dorsal aspect of the left wrist since the age of 10 days. The diagnosis of...
A 50-day-old female child presented with asymptomatic skin colored raised lesion on the dorsal aspect of the left wrist since the age of 10 days. The diagnosis of cutaneous mastocytoma was made based upon clinical and histopathological features.
PubMed: 25484432
DOI: 10.4103/0019-5154.143588 -
Indian Journal of Dermatology,... 2014
Topics: 5-alpha Reductase Inhibitors; Ainhum; Callosities; Color; Constriction, Pathologic; Dutasteride; Educational Measurement; Finasteride; Glomus Tumor; Humans; Hyperpigmentation; Lichen Planus; Mastocytoma; Pemphigoid, Bullous; Phototherapy; Pityriasis Rosea; Skin Diseases; Skin Neoplasms; Sweat Gland Diseases; Warts
PubMed: 25543337
DOI: 10.4103/0378-6323.144226 -
PLoS Genetics Nov 2015Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing...
Canine mast cell tumours (CMCT) are one of the most common skin tumours in dogs with a major impact on canine health. Certain breeds have a higher risk of developing mast cell tumours, suggesting that underlying predisposing germ-line genetic factors play a role in the development of this disease. The genetic risk factors are largely unknown, although somatic mutations in the oncogene C-KIT have been detected in a proportion of CMCT, making CMCT a comparative model for mastocytosis in humans where C-KIT mutations are frequent. We have performed a genome wide association study in golden retrievers from two continents and identified separate regions in the genome associated with risk of CMCT in the two populations. Sequence capture of associated regions and subsequent fine mapping in a larger cohort of dogs identified a SNP associated with development of CMCT in the GNAI2 gene (p = 2.2x10-16), introducing an alternative splice form of this gene resulting in a truncated protein. In addition, disease associated haplotypes harbouring the hyaluronidase genes HYAL1, HYAL2 and HYAL3 on cfa20 and HYAL4, SPAM1 and HYALP1 on cfa14 were identified as separate risk factors in European and US golden retrievers, respectively, suggesting that turnover of hyaluronan plays an important role in the development of CMCT.
Topics: Alternative Splicing; Animals; Dog Diseases; Dogs; GTP-Binding Protein alpha Subunit, Gi2; Genetic Predisposition to Disease; Genome-Wide Association Study; Germ-Line Mutation; Mastocytoma; Polymorphism, Single Nucleotide
PubMed: 26588071
DOI: 10.1371/journal.pgen.1005647 -
Veterinary and Comparative Oncology Sep 2020Lymph node (LN) metastasis is a negative prognostic factor in dogs with cutaneous mast cell tumours (cMCTs). While elective lymphadenectomy of metastatic LNs improves...
Lymph node (LN) metastasis is a negative prognostic factor in dogs with cutaneous mast cell tumours (cMCTs). While elective lymphadenectomy of metastatic LNs improves outcome, the benefit of adjuvant medical therapy in dogs with early metastatic (HN2) LNs is debated. The aim of this retrospective multicentre study was to evaluate the therapeutic benefit of adjuvant medical therapy following surgical removal of the primary low-grade cMCT (Patnaik grade 1-2 and Kiupel low-grade) and lymphadenectomy of HN2 LNs by analysing survival rates and patterns of recurrence. Seventy-three dogs were included: 42 received adjuvant medical treatment (chemotherapy and/or kinase inhibitors), and 31 did not. The median follow-up time for medically treated dogs was 619 days: two experienced local recurrence, three nodal relapse and four distant relapse. For dogs undergoing surgery only, the median follow-up time was 545 days. None of them experienced local recurrence, nodal, or distant relapse. Time to progression was significantly shorter in dogs receiving adjuvant medical treatment (P = .021). A similar tendency was observed for overall survival (P = .056). The current study shows that dogs with low-grade cMCTs, that undergo surgical excision of the primary tumour and elective lymphadenectomy of the HN2 regional LN harbour a good prognosis. The use of adjuvant medical treatment in these dogs does not seem to provide any benefit in terms of progression and survival.
Topics: Animals; Chemotherapy, Adjuvant; Dog Diseases; Dogs; Female; Italy; Lymphatic Metastasis; Male; Mastocytosis; Neoplasm Recurrence, Local; Retrospective Studies; Skin Neoplasms; Survival
PubMed: 31930651
DOI: 10.1111/vco.12566 -
PLoS Genetics Mar 2019Mast cell tumours are the most common type of skin cancer in dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown,...
Mast cell tumours are the most common type of skin cancer in dogs, representing a significant concern in canine health. The molecular pathogenesis is largely unknown, but breed-predisposition for mast cell tumour development suggests the involvement of inherited genetic risk factors in some breeds. In this study, we aimed to identify germline risk factors associated with the development of mast cell tumours in Labrador Retrievers, a breed with an elevated risk of mast cell tumour development. Using a methodological approach that combined a genome-wide association study, targeted next generation sequencing, and TaqMan genotyping, we identified a synonymous variant in the DSCAM gene on canine chromosome 31 that is associated with mast cell tumours in Labrador Retrievers. DSCAM encodes a cell-adhesion molecule. We showed that the variant has no effect on the DSCAM mRNA level but is associated with a significant reduction in the level of the DSCAM protein, suggesting that the variant affects the dynamics of DSCAM mRNA translation. Furthermore, we showed that the variant is also associated with mast cell tumours in Golden Retrievers, a breed that is closely related to Labrador Retrievers and that also has a predilection for mast cell tumour development. The variant is common in both Labradors and Golden Retrievers and consequently is likely to be a significant genetic contributor to the increased susceptibility of both breeds to develop mast cell tumours. The results presented here not only represent an important contribution to the understanding of mast cell tumour development in dogs, as they highlight the role of cell adhesion in mast cell tumour tumourigenesis, but they also emphasise the potential importance of the effects of synonymous variants in complex diseases such as cancer.
Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Dog Diseases; Dogs; Genetic Predisposition to Disease; Genome-Wide Association Study; Germ Cells; Germ-Line Mutation; Mast Cells; Mastocytoma, Skin; Mastocytosis, Cutaneous; Risk Factors; Silent Mutation; Skin Neoplasms
PubMed: 30901340
DOI: 10.1371/journal.pgen.1007967