Integrated DNA copy number and gene expression regulatory network analysis of non-small cell lung cancer metastasis

Abstract

Integrative analysis of multi-level molecular profiles can distinguish interactions that cannot be revealed based on one kind of data in the analy-sis of cancer susceptibility and metastasis. DNA copy number variations (CNVs) are common in cancer cells, and their role in cell behaviors and relationship to gene expression (GE) is poorly understood. An integrative analysis of CNV and genome-wide mRNA expression can discover copy number alterations and their possible regulatory effects on GE. This study presents a novel framework to identify important genes and construct potential regulatory networks based on these genes. Using this approach, DNA copy number aberrations and their effects on GE in lung cancer progression were revealed. Specifically, this approach contains the following steps: (1) select a pool of candidate driver genes, which have significant CNV in lung cancer patient tumors or have a significant asso-ciation with the clinical outcome at the transcriptional level; (2) rank important driver genes in lung cancer patients with good prognosis and poor prognosis, respectively, and use top-ranked driver genes to construct regulatory networks with the COpy Number and EXpression In Cancer (CONEXIC) method; (3) identify experimentally confirmed molecular interactions in the constructed regulatory networks using Ingenuity Pathway Analysis (IPA); and (4) visu-alize the refined regulatory networks with the software package Genatomy. The constructed CNV/mRNA regulatory networks provide important insights into potential CNV-regulated transcriptional mechanisms in lung cancer metastasis.