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Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome.

Karlsson, Anna K LU ; Jönsson, Mats; Lauss, Martin LU ; Brunnström, Hans LU ; Jönsson, Per LU ; Borg, Åke LU ; Jönsson, Göran B LU ; Ringnér, Markus LU ; Planck, Maria LU and Staaf, Johan LU (2014) In Clinical Cancer Research 20(23). p.6127-6140
Abstract
Purpose: 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. Experimental Design: 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), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three small cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation... (More)
Purpose: 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. Experimental Design: 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), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three 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 clinicopathological 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 clinicopathological features such as smoking history, and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, including patient outcome. This study highlights 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
20
issue
23
pages
6127 - 6140
publisher
American Association for Cancer Research
external identifiers
  • pmid:25278450
  • wos:000346417400029
  • scopus:84918512244
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-14-1087
language
English
LU publication?
yes
id
b4293778-ae34-41ac-8fcb-4b020839bf22 (old id 4738423)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25278450?dopt=Abstract
date added to LUP
2014-11-05 18:51:25
date last changed
2017-09-03 03:15:58
@article{b4293778-ae34-41ac-8fcb-4b020839bf22,
  abstract     = {Purpose: 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. Experimental Design: 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), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three 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 clinicopathological 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 clinicopathological features such as smoking history, and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, including patient outcome. This study highlights 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.},
  author       = {Karlsson, Anna K and Jönsson, Mats and Lauss, Martin and Brunnström, Hans and Jönsson, Per and Borg, Åke and Jönsson, Göran B and Ringnér, Markus and Planck, Maria and Staaf, Johan},
  issn         = {1078-0432},
  language     = {eng},
  number       = {23},
  pages        = {6127--6140},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-14-1087},
  volume       = {20},
  year         = {2014},
}