title: Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression.
abstract: Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell-cell and cell-matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.
authors.affiliation: Department of Surgery, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9176, USA.
authors.forename: Suhaida A
authors.initials: SA
authors.lastname: Selamat
authors.forename: Brian S
authors.initials: BS
authors.lastname: Chung
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mihaela
authors.initials: M
authors.lastname: Campan
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.forename: Michael N
authors.initials: MN
authors.lastname: Koss
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hagen
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.forename: Stephen
authors.initials: S
authors.lastname: Lam
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Ite A
authors.initials: IA
authors.lastname: Laird-Offringa
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002454:Cell Differentiation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D037541:Galectin 4 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D015894:Genome, Human; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D012907:Smoking / Q000235:genetics / Q000473:pathology; D060449:Wnt Signaling Pathway; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D037541:Galectin 4; C117307:KRAS protein, human; C511927:LGALS4 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins