title: Key epigenetic changes associated with lung cancer development: results from dense methylation array profiling.
abstract: Epigenetic alterations are a common event in lung cancer and their identification can serve to inform on the carcinogenic process and provide clinically relevant biomarkers. Using paired tumor and non-tumor lung tissues from 146 individuals from three independent populations we sought to identify common changes in DNA methylation associated with the development of non-small cell lung cancer. Pathologically normal lung tissue taken at the time of cancer resection was matched to tumorous lung tissue and together were probed for methylation using Illumina GoldenGate arrays in the discovery set (n = 47 pairs) followed by bisulfite pyrosequencing for validation sets (n = 99 pairs). For each matched pair the change in methylation at each CpG was calculated (the odds ratio), and these ratios were averaged across individuals and ranked by magnitude to identify the CpGs with the greatest change in methylation associated with tumor development. We identified the top gene-loci representing an increase in methylation (HOXA9, 10.3-fold and SOX1, 5.9-fold) and decrease in methylation (DDR1, 8.1-fold). In replication testing sets, methylation was higher in tumors for HOXA9 (p < 2.2 × 10 (-16) ) and SOX1 (p < 2.2 × 10 (-16) ) and lower for DDR1 (p < 2.2 × 10 (-16) ). The magnitude and strength of these changes were consistent across squamous cell and adenocarcinoma tumors. Our data indicate that the identified genes consistently have altered methylation in lung tumors. Our identified genes should be included in translational studies that aim to develop screening for early disease detection.
authors.affiliation: Masonic Cancer Center, Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. hhnelson@umn.edu
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.forename: Milica
authors.initials: M
authors.lastname: Kontic
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Wiemels
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Karagas
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Wrensch
authors.forename: Shichun
authors.initials: S
authors.lastname: Zheng
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D014408:Biomarkers, Tumor