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Multi-'omics comparison of lung cancers from current and never smokers Thu, Kelsie L.


Lung cancer is the leading cause of cancer death worldwide and a better understanding of the molecular alterations driving tumour biology is required to improve patient prognosis. This is especially true for never smokers (NS), which account for up to 25% of lung cancer cases globally. As the population of current smokers (CS) decreases due to smoking cessation and prevention initiatives, in the coming decades NS and former smokers (FS) will comprise a greater proportion of cases. We used an integrative 'omics approach to study lung cancer genomes of CS and NS to elucidate differential mechanisms and patterns of gene and pathway disruption likely to contribute to lung tumourigenesis. Lung cancers in CS and NS exhibit different clinical features and are known to preferentially select specific mutations (e.g. EGFR, KRAS, EML4-ALK), suggesting they are distinct diseases. Thus, we hypothesize that lung tumours of CS and NS exhibit disparate patterns of molecular alterations on a genome wide scale, reflecting the assumption that they develop through the differential selection of genes and pathways. A large scale, multi-dimensional, genomics study has yet to be performed and holds great potential to reveal novel insights into the mechanisms of lung tumourigenesis in CS and NS. Therefore, we performed DNA copy number, methylation, gene expression and microRNA expression profiling on a panel of lung adenocarcinoma tumours from CS and NS in an attempt to characterize the genomic and epigenomic landscapes of these tumours. In addition to identifying commonly disrupted genes and pathways, our integrative genomic analysis revealed numerous differences between CS and NS lung tumours including: differing extents of copy number and methylation alterations, different patterns of miRNA disruption, and preferential disruption of genes and cellular pathways. Importantly, some of the prominently disrupted genes that drive deregulation of tumour promoting pathways may represent novel therapeutic targets and intervention points. Collectively, this work provides further evidence that lung tumours of CS and NS develop through different molecular alterations which suggests patients will benefit from specific management strategies tailored to their smoking status.

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