Mutation of p53 Gene and Its Correlation with the Clinical Outcome in Dogs with Lymphoma

Abstract

Background p53 plays a key role in the apoptotic event induced by chemotherapeutic agents. Mutation of p53 gene has been observed in various spontaneous tumors in humans and is associated with a poor prognosis. p53 abnormalities have been evaluated in several tumors in dogs; however, the association of p53 gene mutation with clinical outcome in dogs with lymphoma has not been documented.Hypothesis/ObjectivesThe aim of this study was to examine p53 mutation in canine lymphoma cells and its association with the clinical outcome.AnimalsForty‐three dogs with previously untreated high‐grade lymphoma referred to the University of Tokyo were included in this study.MethodsProspective cohort study. We examined p53 gene (exon 4–8) mutation in the tumor tissues from 43 dogs with lymphoma using PCR‐SSCP (polymerase chain reaction – single‐strand conformational polymorphism) analysis, followed by nucleotide sequencing of the abnormal bands.ResultsOf the 43 dogs, 7 dogs (16%) had p53 mutation, whereas 36 dogs (84%) were devoid of p53 mutation. Overall response rate after remission induction was significantly lower (33% versus 88%, P = .002) in dogs with lymphomas having p53 mutation than those with lymphomas devoid of p53 mutation. Overall survival time was significantly shorter (67 days versus 264 days, P = .004) in dogs with lymphoma with p53 mutation than those with lymphoma retaining wild‐type p53.Conclusion and Clinical ImportanceMutations of p53 gene were detected in a proportion of canine lymphoma cells from untreated dogs and can be associated with a poor prognosis.

HSP90 inhibitors in the context of heat shock and the unfolded protein response: effects on a primary canine pulmonary adenocarcinoma cell line*

“…In general, similar to humans, p53 mutations appear deleterious in canines with cancer [77–79], suggesting that the tumor suppressor functions are affected. Tumors lacking p53 function were susceptible to HSP90 inhibition by 17-DMAG [80], but again, we do not know the impact of the STAR p53 mutation.…”

Molecular Mechanisms of Canine Cancers

“…Of the seven dogs with a p53 mutation, three had a single base insertion and four had a single base substitution-one of the dogs had a synonymous substitution, but all the other substitutions resulted in a changed amino acid sequence. The study suggests that p53 mutations may not be indicative of a specific anatomical subtype of lymphoma [34]. Furthermore, the study did not account for different histologic or immunophenotypic subtypes, so further exploration with more dogs and more detailed subtype classification is needed to determine a correlation between p53 mutations and subtype of lymphoma.…”

“…The study found that out of 43 dogs with various anatomical subtypes of lymphoma, 7 dogs (16%) had mutations in those exons. More specifically, one dog had a mutation in exons 4, 5 and 6, and two dogs each had a mutation in exon 7 and 8 [34]. Of the seven dogs with a p53 mutation, three had a single base insertion and four had a single base substitution-one of the dogs had a synonymous substitution, but all the other substitutions resulted in a changed amino acid sequence.…”

>b<Mutational evaluation of TP53 gene in the canine hepatocellular carcinoma>/b<: a comparative approach

“…We performed the sequencing technique based on the results and methodology reported by York et al (2012). We analyzed the exons 4 to 8 exons, where the the majority of TP53 gene mutation was related in humans and dogs (MAYR et al, 2002;YONEMARU et al, 2007;KOSHINO et al, 2016). Our results showed no TP53 gene mutations in all canine HCC cases; however, we detect some artefacts (noises) in the chromatograms generated by the Sanger technique.…”

“…Hypothesizing that the mutation is in a low percentage of cells, other techniques could be contemplated as the Single Stranded Conformational Polymorphism (HAYASHI, 1991;VELDHOEN et al, 1999;YONEMARU et al, 2007;KOSHINO et al, 2016).…”