Mutations in two genetic regions in dogs explain more than a third of the risk of developing an aggressive form of hematologic cancer, according to a study by Jacquelyn Evans and Elaine Ostrander at the National Human Genome Research Institute in Maryland, United States, and his colleagues. The study, which combined several sequencing techniques to investigate histiocytic sarcoma in retriever dogs, published May 13 in the open access journal PLOS Genetics.
Histiocytic sarcoma is an aggressive cancer of immune cells, and although extremely rare in humans, it affects about one in five flat-coated scavengers. Genome-wide association investigations of 177 affected and 132 unaffected flat-coated retrievers identified two loci – on chromosomes 5 and 19 of the canine genome – associated with histiocytic sarcoma. Whole genome, transcriptome and chromatin immunoprecipitation sequence data (CHiP) revealed that the CFA5 locus contains mutations in the vicinity of a known tumor suppressor gene, PIK3R6. CFA5 also overlaps two loci previously associated with other hematologic cancers in golden retrievers. The risk alleles at the second locus, CFA19, identified by the genome-wide association survey were found to increase the expression of TNFAIP6, a gene involved in cell metastasis. TNFAIP6 has also been previously associated with a poor prognosis for several human cancers.
Together, these two chromosomal regions accounted for 35% of the risk of histiocytic sarcoma in flat-coated scavengers, an unusually strong effect for such a complex trait, say the authors. By studying this rare cancer in domestic dogs, which have a high disease risk and relatively low genetic diversity, the researchers hope to identify candidate genes to develop new diagnostics and therapies for humans.
“This work identifies two regions of the genome that increase the likelihood of a flat-coated retriever developing histiocytic sarcoma, and highlights genes with tumor suppressing functions in each region,” Ostrander adds. “Strategic breeding can be used to reduce the frequency of disease over time, and genetic observations can lead to treatment options for dogs and humans.”
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