Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.

Mathewos Tessema, Christin M. Yingling, Yushi Liu, Carmen S. Tellez, Leander Van Neste, Stephen B Baylin, Steven A. Belinsky

Research output: Contribution to journalArticle

Abstract

Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (≤10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P <0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P <0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.

Original languageEnglish (US)
Pages (from-to)1248-1257
Number of pages10
JournalCarcinogenesis
Volume35
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Genome
decitabine
Methylation
Genes
Lung Neoplasms
trichostatin A
Non-Small Cell Lung Carcinoma
Cell Line
Adenocarcinoma of lung
DNA Methylation
Transcriptome
Epigenomics
Histones
Small Interfering RNA
Biomarkers
Smoking
Demography
Growth
Neoplasms

ASJC Scopus subject areas

  • Cancer Research

Cite this

Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers. / Tessema, Mathewos; Yingling, Christin M.; Liu, Yushi; Tellez, Carmen S.; Van Neste, Leander; Baylin, Stephen B; Belinsky, Steven A.

In: Carcinogenesis, Vol. 35, No. 6, 2014, p. 1248-1257.

Research output: Contribution to journalArticle

Tessema, M, Yingling, CM, Liu, Y, Tellez, CS, Van Neste, L, Baylin, SB & Belinsky, SA 2014, 'Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.', Carcinogenesis, vol. 35, no. 6, pp. 1248-1257. https://doi.org/10.1093/carcin/bgt494
Tessema, Mathewos ; Yingling, Christin M. ; Liu, Yushi ; Tellez, Carmen S. ; Van Neste, Leander ; Baylin, Stephen B ; Belinsky, Steven A. / Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers. In: Carcinogenesis. 2014 ; Vol. 35, No. 6. pp. 1248-1257.
@article{be886eb08d5c4bd7836dd662e8ad42a4,
title = "Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.",
abstract = "Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80{\%} (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20{\%}, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (≤10{\%}, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89{\%} and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P <0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P <0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.",
author = "Mathewos Tessema and Yingling, {Christin M.} and Yushi Liu and Tellez, {Carmen S.} and {Van Neste}, Leander and Baylin, {Stephen B} and Belinsky, {Steven A.}",
year = "2014",
doi = "10.1093/carcin/bgt494",
language = "English (US)",
volume = "35",
pages = "1248--1257",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.

AU - Tessema, Mathewos

AU - Yingling, Christin M.

AU - Liu, Yushi

AU - Tellez, Carmen S.

AU - Van Neste, Leander

AU - Baylin, Stephen B

AU - Belinsky, Steven A.

PY - 2014

Y1 - 2014

N2 - Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (≤10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P <0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P <0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.

AB - Lung cancer in never smokers (NS) shows striking demographic, clinicopathological and molecular distinctions from the disease in smokers (S). Studies on selected genetic and epigenetic alterations in lung cancer identified that the frequency and profile of some abnormalities significantly differ by smoking status. This study compared the transcriptome of lung adenocarcinoma cell lines derived from S (n = 3) and NS (n = 3) each treated with vehicle (control), histone deacetylation inhibitor (trichostatin A) or DNA methylation inhibitor (5-aza-2'-deoxycytidine). Among 122 genes reexpressed following 5-aza-2'-deoxycytidine but not trichostatin A treatment in two or more cell lines (including 32 genes in S-only and 12 NS-only), methylation was validated for 80% (98/122 genes). After methylation analysis of 20 normal tissue samples and 14 additional non-small cell lung cancer cell lines (total 20), 39 genes frequently methylated in normal (>20%, 4/20) and 21 genes rarely methylated in non-small cell lung cancer (≤10%, 2/20) were excluded. The prevalence for methylation of the remaining 38 genes in lung adenocarcinomas from S (n = 97) and NS (n = 75) ranged from 8-89% and significantly differs between S and NS for CPEB1, CST6, EMILIN2, LAYN and MARVELD3 (P <0.05). Furthermore, methylation of EMILIN2, ROBO3 and IGDCC4 was more prevalent in advanced (Stage II-IV, n = 61) than early (Stage I, n = 110) tumors. Knockdown of MARVELD3, one of the novel epigenetically silenced genes, by small interfering RNA significantly reduced anchorage-independent growth of lung cancer cells (P <0.001). Collectively, this study has identified multiple, novel, epigenetically silenced genes in lung cancer and provides invaluable resources for the development of diagnostic and prognostic biomarkers.

UR - http://www.scopus.com/inward/record.url?scp=84905370287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905370287&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgt494

DO - 10.1093/carcin/bgt494

M3 - Article

C2 - 24398667

AN - SCOPUS:84905370287

VL - 35

SP - 1248

EP - 1257

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 6

ER -