This continues our series of blog posts from PLOS Genetics about our monthly issue images. Author Kerstin Lindblad-Toh discusses February’s issue image from Tonomura et al
Author: Kerstin Lindblad-TOH, Professor Uppsala University, Co-Director SciLifeLab Sweden and Director of Vertebrate Genome Biology, Broad Institute of MIT and Harvard.
Competing interests: Kerstin Lindblad-Toh is an author of the article discussed in this blog.
Cancer is a common disease in both humans and dogs, affecting as many as 50% of individuals in both species. Finding genes and mutations affecting both disease onset and progression would allow for a better understanding of disease mechanisms, and the potential for more accurate diagnosis and treatment guidance. In this issue of PLOS Genetics, we identify two new loci associated with two canine cancers and provide insights into their role in the disease mechanisms.
Human and dog cancers similar in type, but more easily mapped in dogs
Dogs and humans suffer from many of the same cancers, including lymphoma, breast cancer, melanoma, bone cancer, and hemangiosarcoma. Some cancers are common in both species, including breast cancers and lymphoma, whereas others such as osteosarcoma and angiosarcoma/hemangiosarcoma are common in dogs but relatively rare in humans. The rarity of these cancers in humans can make them hard to study. Purebred dog breeds are an attractive model for these rare cancers because the breed structure contributes not only to an enrichment for specific cancers in certain breeds, but also to making the gene mapping process more efficient. While in humans thousands or tens of thousands of samples are needed for genome-wide association mapping, in dogs complex diseases such as cancers can be mapped with only a few hundred patients and controls.
Lymphoma and hemangiosarcoma both coupled to reduced T-cell activation
Our study mapped lymphoma and hemangiosarcoma in purebred golden retrievers. Surprisingly, both diseases mapped to two loci on chromosome 5, together accounting for ~20% of the risk for these diseases in golden retrievers. The loci contained several genes, but no mutations changing the protein sequence were found to correlate with the genetic variants associated with the cancer risk. Instead, expression analysis of B-cell lymphomas showed that the two loci affected the expression of multiple genes. One identified risk locus down-regulates several nearby genes including TRPC6, a Ca2+-channel involved in T-cell activation. The second risk locus overlaps the vesicle transport and release gene STX8, but changes the expression of >100 genes spread across the genome. Many of these genes are involved in activating immune cells, particularly T-cells. Thus, the disease mechanism for B-cell lymphoma and hemangiosarcoma appears to act through a dysregulation of the T-cell mediated immune response to the tumor.
Implications of findings
The findings from this study have potential benefits for both human and canine cancer patients. While further work is necessary to identify additional risk factors contributing to the risk for lymphoma and hemangiosarcoma in golden retrievers and other breeds, there is an opportunity to use the current findings to help cancer patients. Since dogs are patients receiving clinical care just like humans, there is a need for both genetic tests that allow the assessment of disease predisposition and diagnosis, as well as the potential for more personalized treatment options based on genetic risk factors. We are therefore examining how these canine inherited risk factors affect the clinical picture, tumor mutations and treatment outcomes for our canine patients, with the hope of developing better disease regimens. Importantly, these cancers have sufficient similarity to their respective human cancers that the same genes and pathways identified in the dog are likely to play a role also in the human cancer. Therefore, clinical trials in dogs showing correlations between genetic risk factors and treatment outcomes could also inform human cancer treatment.
Tonomura, N., Elvers, I., Thomas, R., Megquier, K., Turner-Maier, J., Howald, C., Sarver, A., Swofford, R., Frantz, A., Ito, D., Mauceli, E., Arendt, M., Noh, H., Koltookian, M., Biagi, T., Fryc, S., Williams, C., Avery, A., Kim, J., Barber, L., Burgess, K., Lander, E., Karlsson, E., Azuma, C., Modiano, J., Breen, M., & Lindblad-Toh, K. (2015). Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers PLOS Genetics, 11 (2) DOI: 10.1371/journal.pgen.1004922