A high-dimensional, deep-sequencing study of lung adenocarcinoma in female never-smokers

PLoS One. 2013;8(2):e55596. doi: 10.1371/journal.pone.0055596. Epub 2013 Feb 6.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Case-Control Studies
  • Female
  • Gene Expression Profiling
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Lung Neoplasms / genetics*
  • MicroRNAs / genetics
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Smoking / genetics*

Substances

  • Biomarkers, Tumor
  • MicroRNAs
  • RNA, Messenger

Grant support

This work was funded by grants from the KRIBB Research Initiative Program (S.L.), National Research Foundation of Korea (grant numbers 20110019747 and 20110002321 to S.L. and grant number 20110014992 to WK), GIST Systems Biology Infrastructure Establishment Grant through ERCSB (SL and JK), and RP-Grant 2011 of Ewha Womans University (SC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.