| Summary: | Background: Around the world, lung cancer is the leading cause of cancer-related death and a major public health problem. A diagnosis of lung cancer carries a remarkably poor prognosis, even after years of research into the disease. The advent and availability of tools to survey the genomes and epigenomes of lung cancers is beginning to yield real clues into the molecular nature of the disease. These clues are being turned into new diagnostic and therapeutic tools with increasing regularity. We used modern high-resolution and high-throughput tools to identify novel genes implicated in various lung cancer phenotypes and aspects of lung cancer pathogenesis.
Hypotheses: (1) Combined profiling of lung cancer genomes and epigenomes will identify critical lung cancer genes that are simultaneously affected by DNA copy number and DNA methylation aberrations. (2) The susceptibility locus on chromosome 6q, identified through familial linkage studies, contains an unidentified tumor suppressor gene (3) Key genes involved in lung cancer phenotypes can be identified through the elucidation of discriminating genomic and epigenomic alterations.
Materials/Methods: Genomic and epigenomic data were analyzed independently and pair-wise to identify genes in NSCLC whose alterations are associated with NSCLC risk, development and phenotype. These genomic and epigenomic data were used in conjunction with a multitude of mRNA and protein-level assays to further refine candidate lists and validate their disruption. Targeted molecular silencing of a candidate TSG was used in conjunction with cellular assays to investigate and confirm the role of this gene in NSCLC.
Results: We designed and optimized an experimental/analysis framework for the combined interrogation of epigenomic and genomic data. We used this framework to identify a novel lung cancer tumor suppressor gene, EYA4, that is frequently disrupted in lung cancers, and is associated with NSCLC risk. Following this, we identified subtype-specific genomic and epigenomic alterations with consequent gene expression changes in NSCLC subtypes. Lastly, we identified specific phenotypic characteristics of the subtypes affected by the DNA alterations.
Conclusions: Integrated analysis of the genomes and epigenomes of NSCLC tumors provides a unique approach for the discovery of key cancer-related genes. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate
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