Cargando…

Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression

Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA me...

Descripción completa

Detalles Bibliográficos
Autores principales: Selamat, Suhaida A., Chung, Brian S., Girard, Luc, Zhang, Wei, Zhang, Ying, Campan, Mihaela, Siegmund, Kimberly D., Koss, Michael N., Hagen, Jeffrey A., Lam, Wan L., Lam, Stephen, Gazdar, Adi F., Laird-Offringa, Ite A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396362/
https://www.ncbi.nlm.nih.gov/pubmed/22613842
http://dx.doi.org/10.1101/gr.132662.111
_version_ 1782238107276410880
author Selamat, Suhaida A.
Chung, Brian S.
Girard, Luc
Zhang, Wei
Zhang, Ying
Campan, Mihaela
Siegmund, Kimberly D.
Koss, Michael N.
Hagen, Jeffrey A.
Lam, Wan L.
Lam, Stephen
Gazdar, Adi F.
Laird-Offringa, Ite A.
author_facet Selamat, Suhaida A.
Chung, Brian S.
Girard, Luc
Zhang, Wei
Zhang, Ying
Campan, Mihaela
Siegmund, Kimberly D.
Koss, Michael N.
Hagen, Jeffrey A.
Lam, Wan L.
Lam, Stephen
Gazdar, Adi F.
Laird-Offringa, Ite A.
author_sort Selamat, Suhaida A.
collection PubMed
description Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell–cell and cell–matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations.
format Online
Article
Text
id pubmed-3396362
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Cold Spring Harbor Laboratory Press
record_format MEDLINE/PubMed
spelling pubmed-33963622013-01-01 Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression Selamat, Suhaida A. Chung, Brian S. Girard, Luc Zhang, Wei Zhang, Ying Campan, Mihaela Siegmund, Kimberly D. Koss, Michael N. Hagen, Jeffrey A. Lam, Wan L. Lam, Stephen Gazdar, Adi F. Laird-Offringa, Ite A. Genome Res Research Lung cancer is the leading cause of cancer death worldwide, and adenocarcinoma is its most common histological subtype. Clinical and molecular evidence indicates that lung adenocarcinoma is a heterogeneous disease, which has important implications for treatment. Here we performed genome-scale DNA methylation profiling using the Illumina Infinium HumanMethylation27 platform on 59 matched lung adenocarcinoma/non-tumor lung pairs, with genome-scale verification on an independent set of tissues. We identified 766 genes showing altered DNA methylation between tumors and non-tumor lung. By integrating DNA methylation and mRNA expression data, we identified 164 hypermethylated genes showing concurrent down-regulation, and 57 hypomethylated genes showing increased expression. Integrated pathways analysis indicates that these genes are involved in cell differentiation, epithelial to mesenchymal transition, RAS and WNT signaling pathways, and cell cycle regulation, among others. Comparison of DNA methylation profiles between lung adenocarcinomas of current and never-smokers showed modest differences, identifying only LGALS4 as significantly hypermethylated and down-regulated in smokers. LGALS4, encoding a galactoside-binding protein involved in cell–cell and cell–matrix interactions, was recently shown to be a tumor suppressor in colorectal cancer. Unsupervised analysis of the DNA methylation data identified two tumor subgroups, one of which showed increased DNA methylation and was significantly associated with KRAS mutation and to a lesser extent, with smoking. Our analysis lays the groundwork for further molecular studies of lung adenocarcinoma by identifying novel epigenetically deregulated genes potentially involved in lung adenocarcinoma development/progression, and by describing an epigenetic subgroup of lung adenocarcinoma associated with characteristic molecular alterations. Cold Spring Harbor Laboratory Press 2012-07 /pmc/articles/PMC3396362/ /pubmed/22613842 http://dx.doi.org/10.1101/gr.132662.111 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research
Selamat, Suhaida A.
Chung, Brian S.
Girard, Luc
Zhang, Wei
Zhang, Ying
Campan, Mihaela
Siegmund, Kimberly D.
Koss, Michael N.
Hagen, Jeffrey A.
Lam, Wan L.
Lam, Stephen
Gazdar, Adi F.
Laird-Offringa, Ite A.
Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title_full Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title_fullStr Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title_full_unstemmed Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title_short Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression
title_sort genome-scale analysis of dna methylation in lung adenocarcinoma and integration with mrna expression
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396362/
https://www.ncbi.nlm.nih.gov/pubmed/22613842
http://dx.doi.org/10.1101/gr.132662.111
work_keys_str_mv AT selamatsuhaidaa genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT chungbrians genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT girardluc genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT zhangwei genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT zhangying genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT campanmihaela genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT siegmundkimberlyd genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT kossmichaeln genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT hagenjeffreya genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT lamwanl genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT lamstephen genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT gazdaradif genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression
AT lairdoffringaitea genomescaleanalysisofdnamethylationinlungadenocarcinomaandintegrationwithmrnaexpression