Genomic copy number variation associated with clinical outcome in canine cutaneous mast cell tumors

Jark, Paulo César; Mundin, Deborah B P; Carvalho, Marcelo; Ferioli, Raquel Beneton; Anai, Letícia Abrahão; Marchi, Fábio Albuquerque; Rogatto, Sílvia Regina; Laufer-Amorim, Renée; Tinucci‐Costa, Mirela

doi:10.1016/j.rvsc.2016.11.009

Cited by 12 publications

(11 citation statements)

References 21 publications

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“…In the current study, the canine BR mast cell line exhibited poor overall survival and colony formation using methycellulose-based media; as such, the effect of WWOX restoration on clonogenic survival following IR could not be fully assessed using a standard colony formation assay in this cell line. This cell line-intrinsic finding may reflect potential differences in cell surface protein expression that impacts the formation of clonogenic colonies in the BR cell line, further demonstrating the complicated genetic heterogeneity known in these tumors [ 14 , 51 ]. Although BR cell viability was evaluated via MTT assays, no differences in cellular survival following IR treatment was observed in BR cells overexpressing WWOX.…”

Section: Discussionmentioning

confidence: 99%

Characterization of WWOX expression and function in canine mast cell tumors and malignant mast cell lines

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

Characterization of WWOX expression and function in canine mast cell tumors and malignant mast cell lines

et al. 2020

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“…Chromosomal grouping (on CFA1 and CFA31, respectively) of genes displaying decreased expression in the M MCTs may be indicative of focal deletions in the M MCTs and/or co-ordinated regulation of transcription. The potential for prognostically-relevant molecular classification of canine MCTs based upon copy number aberrations (CNAs) in MCTs has recently been investigated [97, 98]. CNAs were more frequent in tumours from 6 dogs that died within 6 months of diagnosis (although only 4 of the dogs had confirmed metastasis at diagnosis), and specific gene losses ( PTEN and FAS ; CFA26) and gains ( MAPK3 , WNT5B , FGF , FOXM1 and RAD51 ; CFA27) were associated with a shorter survival time [97].…”

Section: Discussionmentioning

confidence: 99%

“…The potential for prognostically-relevant molecular classification of canine MCTs based upon copy number aberrations (CNAs) in MCTs has recently been investigated [97, 98]. CNAs were more frequent in tumours from 6 dogs that died within 6 months of diagnosis (although only 4 of the dogs had confirmed metastasis at diagnosis), and specific gene losses ( PTEN and FAS ; CFA26) and gains ( MAPK3 , WNT5B , FGF , FOXM1 and RAD51 ; CFA27) were associated with a shorter survival time [97]. One of two genes on CFA26 that showed decreased expression in the M MCTs in the present study is located in a ≥1.2Mb CFA26 fragment affected by loss in ~50% of the MCTs from dogs that died within 6 months of diagnosis [97].…”

Section: Discussionmentioning

confidence: 99%

Identification of molecular genetic contributants to canine cutaneous mast cell tumour metastasis by global gene expression analysis

et al. 2018

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Cutaneous mast cell tumours are one of the most common canine cancers. Approximately 25% of the tumours metastasise. Activating c-kit mutations are present in about 20% of tumours, but metastases occur in the absence of mutations. Tumour metastasis is associated with significantly diminished survival in spite of adjuvant chemotherapy. Available prognostic tests do not reliably predict whether a tumour will metastasise. In this study we compared the global expression profiles of 20 primary cutaneous mast cell tumours that metastasised with those of 20 primary tumours that did not metastasise. The objective was to identify genes associated with mast cell tumour metastatic progression that may represent targets for therapeutic intervention and biomarkers for prediction of tumour metastasis. Canine Gene 1.1 ST Arrays were employed for genome-wide expression analysis of formalin-fixed, paraffin-embedded biopsies of mast cell tumours borne by dogs that either died due to confirmed mast cell tumour metastasis, or were still alive more than 1000 days post-surgery. Decreased gene expression in the metastasising tumours appears to be associated with a loss of cell polarity, reduced cell-cell and cell-ECM adhesion, and increased cell deformability and motility. Dysregulated gene expression may also promote extracellular matrix and base membrane degradation, suppression of cell cycle arrest and apoptosis, and angiogenesis. Down-regulation of gene expression in the metastasising tumours may be achieved at least in part by small nucleolar RNA-derived RNA and microRNA-effected gene silencing. Employing cross-validation, a linear discriminant analysis-based classifier featuring 19 genes that displayed two-fold differences in expression between metastasising and non-metastasising tumours was estimated to classify metastasising and non-metastasising tumours with accuracies of 90–100% and 70–100%, respectively. The differential expression of 9 of the discriminator genes was confirmed by quantitative reverse transcription-PCR.

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“…Although c-KIT mutations seem to be the primary contributor to mast cell tumors, other genes have been observed to contribute to a more severe prognosis and shorter survival times. Specific gene losses in PTEN, FAS, and CFA26 and gene gains in MAPK3, WNT5B, FGF, FOXM1, RAD51 and CFA27 are several potential candidate genes that can be examined for their effects on mast cell tumorigenesis [45,53].…”

Section: Mast Cell Tumorsmentioning

confidence: 99%

Molecular Mechanisms of Canine Cancers

Cao¹,

Kouznetsova²,

Tsigelny³

2019

obm genet

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Cancer is the leading cause of death in dogs, and 50 percent of dogs over the age of 10 develop cancer at some point. The most common cancers in dogs include lymphoma, mast cell tumors, osteosarcoma, mammary gland tumors, and melanoma, and many of them share marked similarities with their human counterparts. Although canines are afflicted with many of the same types of cancers as humans, the genetic basis behind these cancers are not as well understood. Thus, the aim of this study is to elucidate some of the molecular mechanisms behind canine cancers. Canine lymphoma mutation patterns generally vary with the type of lymphoma afflicted-B-cell lymphomas have mutations in the alternative NF-kB pathway including MAP3K14, whereas in T-cell lymphomas the mTOR pathway in boxers and cellular metabolism genes in golden retrievers are affected. Mast cell tumors are largely traced to internal tandem duplications and deletions in the juxtamembrane domain of the proto-oncogene c-KIT. In osteosarcoma, mutations in RB1 and TP53 (especially G: C->A:T transitions in exons 4 and 5), as well as CDK4 inhibitors CDKN2A/B are common. Mammary gland tumors are associated with BRCA2 underexpression due to reading frame shift and mutations in BRC repeat 3. Lastly, deletion or underexpression of p16 and PTEN and altered expression of cell-cell adhesion molecules are common factors in the development of melanoma. The genes identified were then studied to identify more key amino acid mutations that changed protein products and promoted tumorigenesis. Genes that altered expression levels of proteins were analyzed separately. Both sets of candidate genes were then analyzed with the Database for Annotation, Visualization, and Integrated Discovery (DAVID) in order to elucidate the molecular pathways involved in canine cancers and identify more genes possibly involved in tumorigenesis. The proposition of this review is that treatments for both canine and human cancers would be enhanced by comparative genomic studies.

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Genomic copy number variation associated with clinical outcome in canine cutaneous mast cell tumors

Cited by 12 publications

References 21 publications

Characterization of WWOX expression and function in canine mast cell tumors and malignant mast cell lines

Characterization of WWOX expression and function in canine mast cell tumors and malignant mast cell lines

Identification of molecular genetic contributants to canine cutaneous mast cell tumour metastasis by global gene expression analysis

Molecular Mechanisms of Canine Cancers

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