title: Genome-wide DNA methylation analyses in lung adenocarcinomas: Association with EGFR, KRAS and TP53 mutation status, gene expression and prognosis.
abstract: BACKGROUND
  DNA methylation alterations are early events in tumorigenesis and important in the regulation of gene expression in cancer cells. Lung cancer patients have in general a poor prognosis, and a deeper insight into the epigenetic landscape in lung adenocarcinoma tumors and its prognostic implications is needed.
  
  
  RESULTS
  We determined whole-genome DNA methylation profiles of 164 fresh frozen lung adenocarcinoma samples and 19 samples of matched normal lung tissue using the Illumina Infinium 450K array. A large number of differentially methylated CpGs in lung adenocarcinoma tissue were identified, and specific methylation profiles were observed in tumors with mutations in the EGFR-, KRAS- or TP53 genes and according to the patients' smoking status. The methylation levels were correlated with gene expression and both positive and negative correlations were seen. Methylation profiles of the tumor samples identified subtypes of tumors with distinct prognosis, including one subtype enriched for TP53 mutant tumors. A prognostic index based on the methylation levels of 33 CpGs was established, and was significantly associated with prognosis in the univariate analysis using an independent cohort of lung adenocarcinoma patients from The Cancer Genome Atlas project. CpGs in the HOX B and HOX C gene clusters were represented in the prognostic signature.
  
  
  CONCLUSIONS
  Methylation differences mirror biologically important features in the etiology of lung adenocarcinomas and influence prognosis.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: mamok@rr-research.no.
authors.forename: Maria Moksnes
authors.initials: MM
authors.lastname: Bjaanæs
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; The K.G. Jebsen Censtre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway. Electronic address: thomas.fleischer@rr-research.no.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleischer
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: Ann.Rita.Halvorsen@rr-research.no.
authors.forename: Ann Rita
authors.initials: AR
authors.lastname: Halvorsen
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, 75010 Paris, France. Electronic address: antoine.daunay@cephb.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Daunay
authors.affiliation: Laboratory for Epigenetics and Environment (LEE), Centre National de Génotypage, CEA - Institut de Génomique, 91000 Evry, France. Electronic address: busato@cng.fr.
authors.forename: Florence
authors.initials: F
authors.lastname: Busato
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway. Electronic address: Steinar.Solberg@oslo-universitetssykehus.no.
authors.forename: Steinar
authors.initials: S
authors.lastname: Solberg
authors.affiliation: Department of Cardiothoracic Surgery, Oslo University Hospital-Rikshospitalet, Oslo, Norway. Electronic address: Lars.Jorgensen@oslo-universitetssykehus.no.
authors.forename: Lars
authors.initials: L
authors.lastname: Jørgensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: Elin.Kure@rr-research.no.
authors.forename: Elin
authors.initials: E
authors.lastname: Kure
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: hege.edvardsen@abbvie.com.
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway. Electronic address: a.l.borresen-dale@medisin.uio.no.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: ot.brustugun@gmail.com.
authors.forename: Odd Terje
authors.initials: OT
authors.lastname: Brustugun
authors.affiliation: Laboratory for Epigenetics and Environment (LEE), Centre National de Génotypage, CEA - Institut de Génomique, 91000 Evry, France. Electronic address: tost@cng.fr.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; The K.G. Jebsen Censtre for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Clinical Molecular Biology and Laboratory Science (EpiGen), Division of Medicine, Akershus University Hospital, Lørenskog, Norway. Electronic address: v.n.kristensen@medisin.uio.no.
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway; Department of Oncology, Oslo University Hospital - The Norwegian Radium Hospital, Oslo, Norway. Electronic address: aslaug.helland@gmail.com.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D015894:Genome, Human; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009664:Norway / Q000453:epidemiology; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: 450K; Adenocarcinoma; CpG; DNA methylation; EGFR; KRAS; LUAD; Lung cancer; NSCLC; Prognosis; TP53; mRNA