Abstract 1760: Mutational landscape of the canine acute myeloid leukemia exome

Abstract

Abstract Over 21,000 newly diagnosed cases of human acute myeloid leukemia (hAML) and 10,000 hAML-related deaths are reported in the United States every year. hAML is considered a highly diverse aggressive hematopoietic malignancy, with over 16 recurrent gene rearrangements, 60 recurrent point mutations, and hundreds of rarely mutated genes. There are large ongoing multi-institutional studies devoted to advancing medical management for hAML by providing targeted therapeutics to patients based on their molecular characteristics. A preclinical spontaneous large animal model for testing novel therapies could accelerate the development of better treatments in people. Dogs spontaneously develop AML with similar clinical features and outcomes. As such, the dog may be a useful pre-clinical model, but little is known about the molecular landscape and/or drivers of canine AML (cAML). The goal of this work was to identify somatic mutation candidates in cAML and determine the overlapping features with hAML. We utilized whole exome sequencing at 300x coverage to identify candidate mutations in 51 cAML samples. Somatic variant calling was performed per the GATK best practice recommendations using Mutect2 and a reference panel of normals (n=77) and a variant call file of canine germline variants. We focused our analysis on novel variants predicted to have a moderate to high impact and that occurred in genes implicated in cancer. At least one variant was identified in genes involved in the RTK/RAS pathway (e.g. NRAS, KRAS, PTPN11, FLT3, KIT) in over 75% of cAML samples, a trend that is also found in people. Additionally, recurrent point mutations were predicted in NRAS and KRAS, and some of which, such as the codon changes G13R and Q61R/H in NRAS, were noted to be shared between hAML and cAML. Mutations in DNMT3A were uncommon (n=3/44) and NPM1 mutations were not identified in our cohort, both of which are common hAML-associated genes. However, mutations in other epigenetic modifiers, such as KDM5C and KDM6A, occurred at a high frequency. This data provides insight into the candidate mutations potentially driving cAML pathogenesis and highlights the overlapping molecular features with hAML. Citation Format: Robert Harris, Evan Conaway, Anne Avery. Mutational landscape of the canine acute myeloid leukemia exome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1760.