A High-Dimensional, Deep-Sequencing Study of Lung Adenocarcinoma in Female Never-Smokers

Sang Cheol Kim, Yeonjoo Jung, Jinah Park, Sooyoung Cho, Chaehwa Seo, Jaesang Kim, Pora Kim, Jehwan Park, Jihae Seo, Jiwoong Kim, Seongjin Park, Insu Jang, Namshin Kim, Jin Ok Yang, Byungwook Lee, Kyoohyoung Rho, Yeonhwa Jung, Juhee Keum, Jinseon Lee, Jungho HanSangeun Kang, Sujin Bae, So Jung Choi, Sujin Kim, Jong Eun Lee, Wankyu Kim, Jhingook Kim, Sanghyuk Lee

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

Background: Deep sequencing techniques provide a remarkable opportunity for comprehensive understanding of tumorigenesis at the molecular level. As omics studies become popular, integrative approaches need to be developed to move from a simple cataloguing of mutations and changes in gene expression to dissecting the molecular nature of carcinogenesis at the systemic level and understanding the complex networks that lead to cancer development. Results: Here, we describe a high-throughput, multi-dimensional sequencing study of primary lung adenocarcinoma tumors and adjacent normal tissues of six Korean female never-smoker patients. Our data encompass results from exome-seq, RNA-seq, small RNA-seq, and MeDIP-seq. We identified and validated novel genetic aberrations, including 47 somatic mutations and 19 fusion transcripts. One of the fusions involves the c-RET gene, which was recently reported to form fusion genes that may function as drivers of carcinogenesis in lung cancer patients. We also characterized gene expression profiles, which we integrated with genomic aberrations and gene regulations into functional networks. The most prominent gene network module that emerged indicates that disturbances in G2/M transition and mitotic progression are causally linked to tumorigenesis in these patients. Also, results from the analysis strongly suggest that several novel microRNA-target interactions represent key regulatory elements of the gene network. Conclusions: Our study not only provides an overview of the alterations occurring in lung adenocarcinoma at multiple levels from genome to transcriptome and epigenome, but also offers a model for integrative genomics analysis and proposes potential target pathways for the control of lung adenocarcinoma.

Original languageEnglish
Article numbere55596
JournalPLoS ONE
Volume8
Issue number2
DOIs
StatePublished - 6 Feb 2013

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