Lymphoma in Australian Border Collies: pedigree and genetic investigations

Abstract

In Australia, Border Collies have higher incidence of lymphoma compared to other breeds. The primary aims of this thesis are to describe clinical characteristics in ABCs, as well as to investigate evidence of heritability and genomic regions associated with the disease. A detailed survey identified 57 ABCs diagnosed with lymphoma. Multicentric, high grade B-cell was identified as the most common form of lymphoma in ABCs. The mean age of diagnosis was 9.16 years, with female dogs being twice as likely to develop lymphoma compared to males. Pedigree analyses revealed clusters of affected individuals: 21 cases descended from two sires and 28 cases shared a common female ancestor, supporting a heritable component of the disease in the breed.Genome-wide association studies have previously identified genomic variants associated with lymphoma risk in other dog breeds.This study examined whether the previously identified 35 at-risk loci in these breeds are also associated with lymphoma risk in ABCs. Analysis of genotypes in 23 cases and 223 controls ABCs revealed no statistically significant associations at these loci, suggesting that germline risk factors for lymphoma differ among breeds.To further explore genetic variants in lymphoma, genotypes of these at-risk loci were investigated in an affected ABC and six of its close family members. None of the genotypes of the at-risk SNPs were present exclusively in the affected dog. Therefore, the previously described at-risk loci showed no indication of segregation with development of lymphoma in this family. GWAS was subsequently performed using these seven cases (an affected ABC and its closely related family) and 216 control cases. The most prominent association signal was located on chromosome 4 (CFA4), spanning a 2.5Mb region. Two cancer related genes, GNG4 and ARID4B were found in the region. GNG4 is linked to CXCR4 signalling pathway, which has been implicated in aggressive B-cell lymphoma in people.