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J Thorac Oncol. 2018 Nov;13(11):1676-1691. doi: 10.1016/j.jtho.2018.07.096. Epub 2018 Aug 16.

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

Author information

1
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Hastings Center for Pulmonary Research, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California; Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan.
3
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Division of Genomic Technologies, RIKEN Center for Life Science Technologies, Yokohama, Kanagawa, Japan.
5
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
6
Lund University, Laboratory Medicine Region Skåne, Department of Clinical Sciences Lund, Pathology, Lund, Sweden.
7
Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan. Electronic address: asaitou-tky@umin.ac.jp.

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 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.

KEYWORDS:

ASCL1; Adenocarcinoma; Lung cancer; NSCLC; Neuroendocrine

PMID:
30121393
DOI:
10.1016/j.jtho.2018.07.096

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