The long term goal of our collaborative effort is to bring precision medicine to the practice of veterinary oncology, using the wealth of genomic data gathered in human cancers as a roadmap. We pioneered the concept of precision medicine in a common but deadly canine tumor, hemangiosarcoma (HSA), whose equivalent in human is angiosarcoma (AS), a rare yet highly fatal disease. We performed whole exome sequencing to investigate the mutation landscape of HSA and identified candidate driver mutations and therapeutic targets (Wang G, etc, 2017). Based on findings from exome sequencing and genomics data on homologous human disease (AS), I developed an amplicon-based targeted resequencing panel, HSA-panel, which allows genotyping of canine HSA at high coverage, high specificity and sensitivity and yet cost-effective. Together, the discovery sequencing and targeted panel sequencing identified candidate driver mutations in more than 90% patients’ samples, suggesting high diagnostic utility (Wang G, etc, unpublished). More importantly, the two most common driver mutations, present in more than 75% of HSA cases (Wang G, etc, unpublished), are great therapeutic targets suitable for pharmacological intervention, with specific inhibitors already in clinical use in humans. These findings offer us opportunities to perform clinical trials of targeted therapies in canine hemangiosarcoma, which may lead to novel and effective treatment options for canine disease, as well as to inform trial design for similar human disease. Our study in hemangiosarcoma serves as proof-of-concept to enable precision medicine in other canine cancers. To this end, I constructed a capture-based comprehensive canine cancer panel, which detects a wide range of mutations in 282 genes known to drive cancer development and covers a total target region of 1.4 mb in canine genome. Our goal is to identify driver mutations and clinically actionable biomarkers in all common canine cancers, to arm veterinary clinicians with better prognostic information, target therapeutic options, and markers to predict treatment response, ultimately enabling precision medicine in canine oncology.
The second part of this presentation will cover:
Somatic mutations accumulate in cells during normal aging. While most mutations are neutral, other mutations provide an advantage that can favor cell growth under certain conditions. In the blood, such non-neutral mutations drive clonal hematopoiesis (CH) in which many or most blood cells carry a common mutation that is detectable by next-generation sequencing. CH increases in prevalence as people age and is largely asymptomatic. However, data suggest that CH can be pro-inflammatory and thus may drive or catalyze a number of age-related disease processes - especially cardiovascular disease and hematologic cancers. Thus, the delineation of CH mutation patterns that predict disease risk has the potential to enable early detection and improvements in disease intervention. We describe CH mutation patterns that inform the risk and timing of acute myeloid leukemia (AML) as many as 17 years prior to diagnosis as well as the development of a new CH detection platform.
1. You will learn about the mutation landscape of a common yet deadly canine tumor, hemangiosarcoma, through whole exome sequencing and targeted panel resequencing
2. You will learn about the identified candidate driver mutations and therapeutic targets in over 75% of cases