Dissertation/Thesis Abstract

Molecular Heterogeneity and Drivers of Tumor Evolution in Liver Cancer
by Craig, Amanda Jean, Ph.D., Icahn School of Medicine at Mount Sinai, 2019, 178; 13902124
Abstract (Summary)

Liver cancer is the fifth most commonly diagnosed cancer and the fourth leading cause of cancer related deaths worldwide. Clonal evolution of a tumor ecosystem depends not only on somatic mutations driving uncontrolled growth, but also on a full array of selection pressures that are principally immune and treatment mediated. Here I integrate data from RNA-seq, targeted DNA sequencing, and SNP array technologies across multiple regions of liver cancer specimens to map spatio-temporal interactions between cancer and immune cells. I interrogate how these interactions reflect intra-tumor heterogeneity (ITH) by correlating regional neo-epitope and viral antigen burden with the magnitude and clonality of the regional adaptive immune response. Regional expression of passenger mutations dominantly recruits adaptive responses as opposed to hepatitis B virus and cancer-testis antigens. I detect lymphocyte clonal expansions in distant regions of the same tumor nodule. Leveraging the TCGA liver cancer dataset, I show that an ITH-based gene signature improves single-biopsy patient survival predictions. An expression survey of 38,553 single cells across 7 regions of 2 patients further reveals significant and highly regionally dependent heterogeneity of transcription factor activity in liver cancer cells. Overall, these data quantify the scale of transcriptomic ITH and how the different components of the liver cancer ecosystem interact during cancer evolution.

While cancer-testis antigens (CTAs) appear lowly immunogenic in liver cancer, there were patients who showed an extreme overexpression of these genes with regional variation. Specifically, approximately one third of patients from a cohort of 228 HCC samples appear to be high expressers of the CTA MAGEA3/6. MAGEA3/6 was determined to be a key causal driver of a major regulatory sub-network inferred from TCGA LIHC-HCC data. Further, MAGEA3/6 expression is also correlated with worse overall survival, poor differentiation tumor status and several gene signatures of poor prognosis. Experimentally, in a MYC; TP53 mouse model of liver cancer, the additional over-expression of MAGEA3/6 led to a significantly shorter overall survival. These data suggest an active role in liver cancer progression for MAGEA3/6.

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Indexing (document details)
Advisor: Villanueva, Augusto
Commitee: O'Connell, Matthew, Pfleger, Cathie, Lujambio, Amaia, Friedman, Scott
School: Icahn School of Medicine at Mount Sinai
Department: Cancer Biology
School Location: United States -- New York
Source: DAI-B 81/2(E), Dissertation Abstracts International
Subjects: Oncology, Molecular biology, Immunology
Keywords: Hepatocellular carcinoma, Immunogenomics, Liver cancer, Tumor heterogeneity
Publication Number: 13902124
ISBN: 9781085631617
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