Cancer Research Collaborative Project

Funded In Part by the Golden Retriever Foundation GRADUATE Challenge

The abstracts presented below explain two grants which have been funded through the CHF-GRF Cancer Collaborative. The decision to recommend funding of two grants has to do with the complementary nature of these grants, the rigor of the science and the exceptional collaborative teams that will be conducting the work.

Grant 1918 covers the emerging importance of epigenetics, which is the study of the heritable changes in gene expression caused by alterations in DNA methylation rather than changes in the underlying DNA sequence. Epigenetic regulation explains how two identical genotypes can give rise to different phenotypes in response to the same environmental stimulus. 

Grant 1889 covers the ongoing search for heritable risk alleles from a well-established, highly productive team of investigators. Separately these grants will have impact; together the synergy of this research will substantially hasten our understanding of cancer pathogenesis and get us much closer to preventing disease from occurring. 

1918-G: Discovery of novel protein, blood, and epigenetic biomarkers of lymphoma risk, classification, and prognosis in Golden Retrievers 

Investigators/Institutions: Dr. Jeffery N. Bryan, DVM, MS, PhD, of University of Missouri, Columbia; Dr. Anne Avery DVM, PhD, Colorado State University; Dr. Heather Wilson-Robles, DVM, Texas A&M University

Grant Period: June 1, 2013 – May 31, 2016

Lymphoma strikes 1 in 8 Golden Retrievers, making them one of the most commonly affected breeds. Dr. Jeffrey Bryan, in collaboration with Dr. Anne Avery (Colorado State University) and Dr. Heather Wilson-Robles (Texas A&M University), will improve diagnostic, classification, and prognostic ability using state of the art technology to characterize the B cell lymphomas of Golden Retrievers. Through joint CHF/GRF funding, these investigators will identify aberrant epigenetic (DNA methylation) changes in lymphoma cells to develop biomarkers of each class of lymphoma, and in turn, identify new therapy targets for affected Golden Retrievers. More significantly, because DNA methylation changes occur so early in the process of cancer formation, these investigators hypothesize that they could serve as biomarkers of risk, allowing medicine or diet to prevent lymphoma in Golden Retrievers before it develops. Finally, they propose to fully phenotype cancer stem cells in lymphoma by surface markers and DNA methylation changes for the purpose of targeting those cells which feed cancer metastasis. Individually each project advances a current frontier of research. By performing them in parallel, the discoveries made in each project can be combined, correlated, and translated into biomarkers of risk, diagnosis, and prognosis to advance the prevention and management of lymphoma in Golden Retrievers. Based on data from other species these investigators expect epigenetic changes to occur across all breeds and anticipate this study will open the door for a deeper understanding of cancer in all dogs.

1889-G: Developing Markers to Diagnose and Guide Cancer Treatment in Golden Retrievers Based on Newly Discovered Heritable and Acquired Mutations 

Investigators/Institutions: Dr. Jaime F Modiano, VMD, PhD, of University of Minnesota; Dr. Matthew Breen, PhD, North Carolina State University; Dr. Kerstin Lindblad-Toh, PhD, Broad Institute of MIT and Harvard.

Grant Period: June 1, 2013 – May 31, 2016

Lymphoma and hemangiosarcoma are major health problems in Golden Retrievers, causing both suffering and premature death. After years of collaboration, Dr. Jaime Modiano (University of Minnesota), Dr. Matthew Breen (North Carolina State University) and Dr. Kerstin Lindblad-Toh (Broad Institute of MIT and Harvard) have made several ground breaking discoveries: 1) they have identified several regions of the genome that contain genetic heritable risk factors for lymphoma and hemangiosarcoma, and 2) they have identified somatic mutations in tumors that occur recurrently in both cancers, some of which are linked to duration of remission when treated with standard of care. These results indicate that a few heritable genetic risk factors account for as much as 50% of the risk for these cancers. These investigators now believe their findings offer the potential to develop strategies for risk assessment in individual dogs, as well as the potential to manage risk across the population as a whole. Further, these inherited risk factors and tumor mutations point to pathways that have been implicated in the pathogenesis of lymphoma and hemangiosarcoma, and thus should inform the development of targeted therapies. Through joint CHF-GRF funding, these investigators will identify precise mutations for the heritable genetic risk factors and will validate markers (mutations) that can be used to determine risk at the heritable loci in a large independent population of Golden Retrievers from the USA and from Europe. Their ultimate goal is to develop robust risk prediction tools, and hopefully, an accompanying DNA test. As has been the case with most genetic-based studies, data are expected to be transferable across all breeds, enabling the future search for cancer risk factors in all dogs to be rapid and focused.