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ASCO Presenter Touts Comparative Genomics with Dog, Sea Lion Models as Source of Cancer Clues

CHICAGO (GenomeWeb) – Researchers are continuing to expand the repertoire of animal models used to study the genetic basis of various cancers, attendees heard here this weekend at the annual American Society of Clinical Oncology meeting.

As part of a session on evolution, medicine, and cancer, North Carolina State University genomics researcher Matthew Breen described the rationale behind his team's comparative oncology research, focusing on findings from molecular studies done on bladder cancers in dogs and sea lions.

Researchers have long relied on mouse models for scrutinizing cancer. But Breen noted that mice actually have relatively low rates of spontaneous cancer, necessitating genetic manipulation or other strategies to induce disease before it can be studied.

In contrast, he explained, it's increasingly clear that other animals — including domestic dogs — do get spontaneous malignancies, perhaps through pathways that resemble those involved in human disease.

Dogs also share the same exposures as their human companions, Breen noted, hinting that the roughly 83 million dogs who live in American households may be poised to aid in the search for cancer-related genes and related environmental factors that are relevant to human disease.

Indeed, more or less all of the cancers that occur in humans also turn up in dogs, Breen said. And some breeds are especially prone to certain cancer types, suggesting there might be inherited cancer predisposition sequences that can be teased out in dog studies.

In a paper published in PLOS Genetics earlier this year, for example, Breen and colleagues from the US and Sweden described findings from a genome-wide association study that uncovered immune-related loci linked to canine B-cell lymphoma and hemangiosarcoma in Golden Retrievers — a breed at 6 percent and 20 percent risk of the blood cancers, respectively.

Members of the same team detected dozens of sites in the dog genome that showed ties to inherited osteosarcoma in greyhounds, Rottweilers, and Irish wolfhounds through another GWAS reported in Genome Biology in December 2013.

Dogs have been the focus of other cancer-related studies, too. In a 2013 study in PLOS One, investigators at the University of Göttingen and Chronix Biomedical highlighted the possibility of using droplet digital PCR to pick up chromosomal breakpoints coinciding with canine mammary tumors in circulating cell-free tumor DNA from dog blood samples.

For his presentation at ASCO, Breen first described findings from a molecular cytogenetic study of chronic myeloid leukemia that unearthed a fusion between the dog versions of the BCR and ABL genes that's akin to the classic AML-causing "Philadelphia chromosome" in humans.

Not only did all of the canine CML tumors contain the BCR-ABL fusion, he noted, but dogs with CML seemed to respond to treatment with the type of tyrosine kinase inhibitor used to treat human forms of the disease.

Breen also discussed a bladder cancer study that began in dogs and was ultimately validated in sea lions.

There, he and his colleagues did copy number profiling on dogs with a form of bladder cancer called transitional cell carcinoma (TCC) or urothelial cell carcinoma, which is suspected in millions of dogs each year but remains difficult to diagnose.

In the hopes of better understanding human forms of this bladder cancer — and developing urine-based assays for the disease in dogs — the team did copy number profiling on canine TCC cases.

Rather than limiting their analyses to dog chromosomes, though, the researchers aligned the dog sequences so that they coincided with the human chromosomes carrying corresponding sequence homologues.

After this "recoding" of the dog data, Breen explained, the bladder cancer-associated gains, losses, and amplifications found on chromosomes 13, 19, and 36 in the dog genome fell in and around human copy number changes that have been implicated in urothelial carcinoma.

To rule out coincidental overlap between these sites, the researchers turned to yet another animal: the California sea lion.

Hundreds of the sea lions that wash ashore in that state each year end up living at marine centers, Breen explained, where a significant proportion of the animals develop very aggressive urogenital sarcomas.

Copy number tests on these sea lion tumors again unearthed gains and losses that, when reorganized to match human chromosome patterns, roughly corresponded to copy number changes that characterize human and dog bladder cancers, he said.

Bolstered by such results, Breen and his colleagues are now developing additional DNA and RNA resources in dogs and other animals.

Breen is on the board of the Canine Comparative Oncology and Genomics Consortium and is a charter member of the Sea Lion Cancer Consortium. He also pointed out opportunities to participate in comparative cancer research through the National Cancer Institute's Comparative Oncology Program.

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