Naoya Miyashita1, Masafumi Horie2, Hiroshi I Suzuki3, Masahito Yoshihara4, Dijana Djureinovic5, Johan Persson5, Hans Brunnström6, Cecilia Lindskog5, Hedvig Elfving5, Patrick Micke5, Akira Saito7, Takahide Nagase1. 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.
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.
Authors: Bregtje C M Hermans; Jules L Derks; Lisa M Hillen; Irene van der Baan; Esther C van den Broek; Jan H von der Thüsen; Robert-Jan van Suylen; Peggy N Atmodimedjo; T Dorine den Toom; Cecile Coumans-Stallinga; Wim Timens; Winand N M Dinjens; Hendrikus J Dubbink; Ernst-Jan M Speel; Anne-Marie C Dingemans Journal: Int J Cancer Date: 2021-11-10 Impact factor: 7.316
Authors: Jasna Metovic; Anna La Salvia; Ida Rapa; Francesca Napoli; Nadia Birocco; Maria Pia Bizzi; Rocio Garcia-Carbonero; Libero Ciuffreda; Giorgio Scagliotti; Mauro Papotti; Marco Volante Journal: Endocr Pathol Date: 2022-05-24 Impact factor: 4.056