Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1–Positive Lung Adenocarcinomas

Miyashita, Naoya ; Horie, Masafumi ; Suzuki, Hiroshi I. ; Yoshihara, Masahito ; Djureinovic, Dijana ; Persson, Johan ; Brunnström, Hans LU orcid ; Lindskog, Cecilia ; Elfving, Hedvig and Micke, Patrick , et al. (2018) In Journal of Thoracic Oncology 13(11). p.1676-1691
Abstract

Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype... (More)

Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adenocarcinoma, ASCL1, Lung cancer, Neuroendocrine, NSCLC
in
Journal of Thoracic Oncology
volume
13
issue
11
pages
1676 - 1691
publisher
Elsevier
external identifiers
  • scopus:85053917253
  • pmid:30121393
ISSN
1556-0864
DOI
10.1016/j.jtho.2018.07.096
language
English
LU publication?
yes
id
01d37577-d6bd-414b-9c8e-96b5e7aa0742
date added to LUP
2018-10-26 11:19:43
date last changed
2021-10-06 02:47:25
@article{01d37577-d6bd-414b-9c8e-96b5e7aa0742,
  abstract     = {<p>Introduction: A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute family bHLH transcription factor 1 (ASCL1), common to high-grade neuroendocrine tumors, small-cell lung cancer and large cell neuroendocrine carcinoma. Methods: The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by using recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas. Results: The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor EGFR mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 protein expression. Genome-wide methylation analysis showed global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. Conclusions: These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.</p>},
  author       = {Miyashita, Naoya and Horie, Masafumi and Suzuki, Hiroshi I. and Yoshihara, Masahito and Djureinovic, Dijana and Persson, Johan and Brunnström, Hans and Lindskog, Cecilia and Elfving, Hedvig and Micke, Patrick and Saito, Akira and Nagase, Takahide},
  issn         = {1556-0864},
  language     = {eng},
  number       = {11},
  pages        = {1676--1691},
  publisher    = {Elsevier},
  series       = {Journal of Thoracic Oncology},
  title        = {An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1–Positive Lung Adenocarcinomas},
  url          = {http://dx.doi.org/10.1016/j.jtho.2018.07.096},
  doi          = {10.1016/j.jtho.2018.07.096},
  volume       = {13},
  year         = {2018},
}