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Lymphoma Mutations Modeled Through Genomic Analysis of Dog Breeds, BoG Speaker Reports

COLD SPRING HARBOR, NY (GenomeWeb) – A team from the US, Sweden, and the UK has been sifting through germline and tumor sequences from different breeds of dogs that are affected with the same cancer types in an effort to ultimately untangle germline variant effects on tumor mutations in human cancers.

At the Biology of Genomes meeting here yesterday, Broad Institute and Uppsala University researcher Ingegerd Elvers reported on early findings from a study of dozens of cocker spaniels, golden retrievers, and boxers that spontaneously developed T-cell lymphoma or B-cell lymphoma.

At least some of the dog lymphoma tumors contained genes that are known to be mutated in human lymphomas, Elvers noted, though other mutated genes were new or linked to other human cancer types.

The high levels of between-breed genetic diversity, coupled with inbreeding within breeds, have contributed to the wide range of disease susceptibility patterns that exist in dogs. Some breeds have far higher-than-usual levels of certain diseases than others, while being less prone to other conditions, she explained.

"Due to species and breed creation bottlenecks and artificial breeding for phenotypic factors, dog breeds display strong genetic diversity between breeds but very limited diversity within breeds," Elvers and co-authors wrote in the abstract for the presentation.

With that in mind, the team set out to characterize lymphoma- and germline-specific variants in matched tumor and normal samples in 10 cocker spaniels with B-cell lymphoma, 54 B-cell lymphoma-affected golden retrievers, 25 golden retrievers with T-cell lymphoma, and 16 boxers with T-cell lymphoma.

Elvers noted that canine lymphoma cases share clinical and histological features with human lymphoma, though the dog cancers tend to progress more quickly. Such similarities suggest it may be possible to tease apart interactions between germline variation and tumor mutations in dogs by taking advantage of breed structure and specific cancer susceptibilities within breeds.

To explore this possibility, the team sequenced protein-coding portions of the dog genome that had been captured with a canine exome kit, before aligning the resulting exome sequences to the dog reference genome for subsequent annotation steps.

In general, the researchers found tumors from dogs in the T-cell lymphoma-prone breeds — the golden retrievers and boxers — shared fewer recurrent mutations than B-cell tumors, which affected golden retrievers and cocker spaniels.

Although they did see some genes that were recurrently mutated in one breed or the other, a handful of the same genes were significantly mutated in B-cell lymphomas from golden retrievers and cocker spaniels, including the ubiquitin ligase gene FBXW7 — a gene implicated in human forms of B-cell lymphoma.

In the T-cell lymphoma tumors, meanwhile, the team found that nearly half of tumors in boxers had mutations affecting the tumor suppressor gene PTEN, while the golden retriever T-cell lymphomas had other alterations.

The analysis also unearthed apparent differences between dog breed with respect to the types of mutations and mutation frequencies. While tumor samples from each breed contained comparable numbers of non-synonymous mutations within each tumor type, for example, the golden retrievers had about one-third fewer mutations overall than the cocker spaniels.

"Analysis of breed specific germline and somatic variation suggest differential DNA repair activity in different breeds," Elvers and her co-authors wrote.

Because canine lymphoma treatments resemble those used in humans, the researchers plan to expand their analyses to consider possible treatment response and outcome differences related to dog breed and genetic background.