Characterization of Marek’s Disease Tumors for Driver Mutations

Marek’s disease (MD), a virally-induced lymphoproliferative disease of chickens characterized by T cell lymphomas, costs the worldwide poultry industry an estimated $2+ billion annually. Despite control measures like widespread usage of MD vaccines and biosecurity, new and more virulent field strains of Marek’s disease virus (MDV), the causative agent, have repeatedly arisen resulting in disease outbreaks. Enhancing genetic resistance is an attractive alternative and, therefore, there is a critical need to understand how MDV induces neoplastic transformation. To identify somatic mutations, highly inbred experimental White Leghorn lines that were MD resistant or susceptible were intermated to produce F₁ chicks that were challenged with MDV, and the subsequent tumors and matching normal tissues from each individual collected. To date, most samples have been screened to generate three primary datasets: (1) whole genome sequencing analysis, (2) whole transcriptome sequencing analysis, and (3) cytogenetic analysis to identify MDV integration sites. Thus far, characterization of 26 MD tumors with multiple algorithms has repeatedly identified ~300 somatic single nucleotide variants (SNVs) and ~50 non-synonymous mutations per tumor sample. Frequently mutated genome targets shared between tumors include tumor suppressor genes (TSGs) containing loss-of-function mutations. Transcriptome analysis shows differential gene expression and deregulation of many cancer-associated genes and pathways (e.g., MAPK, cell cycle, apoptosis). Collectively, these data demonstrate how somatic mutations in MD tumors contribute to tumor genesis and progression, and made aid in genomic selection for MD resistance.