POT1 mutations are frequent and associated with Ki-67 index in canine diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) represents one of the most frequent and deadliest neoplasia in dogs worldwide and is characterized by a remarkable degree of clinical heterogeneity, with poor chances to anticipate the outcome. Even if in the last years some recurrently mutated genes have been identified, the genetic origin of canine DLBCL (cDLBCL) is not yet completely understood. The aim of the present study was to assess the prevalence of POT1 mutations in cDLBCL and to elucidate the role of such gene in the pathogenesis of this tumor. Mutations in POT1 were retrieved in 34% of cases, in line with previous reports, but no significant associations with any clinico-pathological variable were identified. Likewise, POT1 mutations are not predictive of worse prognosis. Interestingly, Ki-67 index was significantly higher in dogs harboring POT1 mutations compared to wild-type ones. These results suggest that POT1 mutations may exert their pathogenic role in cDLBCL by promoting cellular proliferation.

Keywords: Ki-67; POT1; diffuse large B-cell lymphoma; dog; mutation.

Figure 1

POT1 somatic mutations. The upper panel shows dogs harboring a protein coding somatic mutation in POT1 gene. Frameshift and non-sense variants are both indicated as truncating mutations. The Oncoprint was generated using the Oncoprinter tool from cBioPortal (https://www.cbioportal.org/oncoprinter). The lower panel shows the lollipop plot of mutations retrieved in the study cohort. The height of each bar represents the frequency at which each mutation occurred. Functional protein domains are also depicted. The lollipop plot was generated using the maftools R package and modified to adapt to canine protein (F1P716_CANLF from UniProt).

Figure 2

Summary of POT1 mutations identified in the present study. (A) Percentage of single base substitutions; (B) Percentage of mutations belonging to each class.

Figure 3

Association between POT1 mutational status and Ki-67 index. IHC score for Ki-67 is reported as number of positive cells per 1,000 randomly selected cells excluding necrotic areas. The difference between median Ki-67 index among POT1 mutated and wild-type dogs was assesses through Mann-Whitney test (statistical significance set at P < 0.05).