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An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1-Positive Lung Adenocarcinomas
Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan.
Univ Tokyo, Grad Sch Med, Dept Resp Med, Tokyo, Japan;Univ Southern Calif, Hastings Ctr Pulm Res, Div Pulm Crit Care & Sleep Med, Dept Med,Keck Sch Med, Los Angeles, CA USA;RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.
MIT, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA.
RIKEN Ctr Life Sci Technol, Div Genom Technol, Yokohama, Kanagawa, Japan.ORCID-id: 0000-0002-8915-9282
Vise andre og tillknytning
2018 (engelsk)Inngår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 13, nr 11, s. 1676-1691Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

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 thatASCL1 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.

sted, utgiver, år, opplag, sider
ELSEVIER SCIENCE INC , 2018. Vol. 13, nr 11, s. 1676-1691
Emneord [en]
Lung cancer, Adenocarcinoma, Neuroendocrine, ASCL1, NSCLC
HSV kategori
Forskningsprogram
Patologi
Identifikatorer
URN: urn:nbn:se:uu:diva-371088DOI: 10.1016/j.jtho.2018.07.096ISI: 000450088600020PubMedID: 30121393OAI: oai:DiVA.org:uu-371088DiVA, id: diva2:1272740
Forskningsfinansiär
Knut and Alice Wallenberg FoundationSwedish Cancer SocietyTilgjengelig fra: 2018-12-19 Laget: 2018-12-19 Sist oppdatert: 2019-03-29bibliografisk kontrollert

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