title: Genome Wide Methylome Alterations in Lung Cancer.
abstract: Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.
authors.affiliation: Department of Medicine/Pulmonary, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Nandita
authors.initials: N
authors.lastname: Mullapudi
authors.affiliation: Department of Bioinformatics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Melissa
authors.initials: M
authors.lastname: Fazzari
authors.affiliation: Department of Medicine/Pulmonary, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Han
authors.affiliation: Department of Medicine/Pulmonary, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Miao K
authors.initials: MK
authors.lastname: Shi
authors.affiliation: Department of Medicine/Pulmonary, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Gaby
authors.initials: G
authors.lastname: Marquardt
authors.affiliation: Department of Epidemiology & Population Health, Division of Biostatistics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular &Thoracic Surgery, Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Keller
authors.affiliation: Department of Pathology, Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Changcheng
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Montefiore Medical Center, Bronx, New York, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Locker
authors.affiliation: Department of Medicine/Pulmonary, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.|Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Simon D
authors.initials: SD
authors.lastname: Spivack
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic