title: Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome.
abstract: OBJECTIVE
  Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear.
  
  
  METHODS
  Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles.
  
  
  RESULTS
  Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome.
  
  
  CONCLUSIONS
  Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Mats
authors.initials: M
authors.lastname: Jönsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Brunnström
authors.affiliation: Department of Thoracic Surgery, Lund University and Skåne University Hospital, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Jönsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Planck
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. johan.staaf@med.lu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D016000:Cluster Analysis; D018899:CpG Islands; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015203:Reproducibility of Results; D012307:Risk Factors; D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins