DEVELOPING METHODS TO DETECT DNA REPAIR DEFECTS IN A DIVERSE POPULATION

Primary liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is one of the fastest growing cancer types. Although HCCs and CCAs are anatomically co-localized, they have distinct etiologic and genomic characteristics that varies vastly in clinical outcome and response to therapy. The Cancer Genome Atlas (TCGA) identified a subset of HCC tumors with CCA genomic features, suggesting these tumors may be a separate HCC class based on their relatedness to CCA. While multiple groups have performed molecular characterization of liver tumors in an effort to identify subtypes, few have investigated beyond gene expression and/or mutations, in an integrated HCC and CCA analysis, or in association with outcomes and liver specific processes (e.g., liver regeneration). This is particularly important because DNA repair dysfunction and liver regeneration are tightly coupled processes implicated in impaired genomic integrity and hepatocarcinogenesis. Particularly, dysregulation of these pathways may be linked to chemoresistance. Given the lack of targeted therapeutic modalities for HCC and ongoing efforts to reduce recurrence, further characterizing and subdividing HCC based on multiple pathway interactions and identification of biomarkers that are associated with repair-mediated survival represents an unmet clinical need. To address this knowledge gap, the current body of work leveraged two TCGA studies, HCC and CCA, both detailed in molecular, histological, and clinical data across multiple platforms. Through a multi-omic approach, chapter 2 of this study characterized distinct HCC subclasses utilizing an integrated TCGA HCC and CCA dataset to gain insights into biology. Chapter 3 leveraged RNA expression profiling to investigate DNA repair in association with mitotic and regenerative signatures, and clinicopathologic variables in TCGA HCC study. This work identified three molecularly distinct HCC subclasses associated with viral infection and progression-free survival. In addition, RNA-based classification of DNA repair identified heterogeneity of repair pathways in HCC tumors, and a subset of tumors with substantial disrupted liver biology and poor outcomes. Collectively, this work contributes novel findings about HCC features and repair dysfunction that dictate prognosis, and highlights the importance of developing class specific biomarkers and targeted therapies.Doctor of Philosoph

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma

DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways. The low-repair group had lower grade and retained the expression of classical liver markers, whereas the high-repair group had more clinically aggressive features, increased p53 mutant-like gene expression, and high liver regenerative gene expression. These pronounced features overshadowed the variation in the low-repair subset, but when considered separately, the low-repair samples included three subgroups: L1, L2, and L3. L3 had high DNA repair expression with worse progression-free (HR 1.24, 95% CI 0.81–1.91) and overall (HR 1.63, 95% CI 0.98–2.71) survival. High-repair outcomes were also significantly worse compared with the L1 and L2 groups. HCCs vary in DNA repair expression, and a subset of tumors with high regeneration profoundly disrupts liver biology and poor prognosis