title: ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation.
abstract: ASCL1 is an important regulatory transcription factor in pulmonary neuroendocrine (NE) cell development, but its value as a biomarker of NE differentiation in lung adenocarcinoma (AD) and as a potential prognostic biomarker remains unclear. We examined ASCL1 expression in lung cancer samples of varied histologic subtype, clinical outcome and smoking status and compared with expression of traditional NE markers. ASCL1 mRNA expression was found almost exclusively in smokers with AD, in contrast to non-smokers and other lung cancer subtypes. ASCL1 protein expression by immunohistochemical (IHC) analysis correlated best with synaptophysin compared with chromogranin and CD56/NCAM. Analysis of a compendium of 367 microarray-based gene expression profiles in stage I lung adenocarcinomas identified significantly higher expression levels of the RET oncogene in ASCL1-positive tumors (ASCL1(+)) compared with ASCL1(-) tumors (q-value <10(-9)). High levels of RET expression in ASCL1(+) but not in ASCL1(-) tumors was associated with significantly shorter overall survival (OS) in stage 1 (P=0.007) and in all AD (P=0.037). RET protein expression by IHC had an association with OS in the context of ASCL1 expression. In silico gene set analysis and in vitro experiments by ASCL1 shRNA in AD cells with high endogenous expression of ASCL1 and RET implicated ASCL1 as a potential upstream regulator of the RET oncogene. Also, silencing ASCL1 in AD cells markedly reduced cell growth and motility. These results suggest that ASCL1 and RET expression defines a clinically relevant subgroup of ∼10% of AD characterized by NE differentiation.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: F
authors.initials: F
authors.lastname: Kosari
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Ida
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: M-C
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
authors.forename: I V
authors.initials: IV
authors.lastname: Kovtun
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: J L S
authors.initials: JL
authors.lastname: Klein
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: S
authors.initials: S
authors.lastname: Erdogan
authors.affiliation: Department of Surgery and Advanced Genomic Technology Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Tomaszek
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: L C
authors.initials: LC
authors.lastname: Bolette
authors.affiliation: Advanced Genomic Technology Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Kolbert
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Surgery and Advanced Genomic Technology Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Wigle
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Vasmatzis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D016000:Cluster Analysis; D005500:Follow-Up Studies; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D055099:Neuroendocrine Cells / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D012907:Smoking
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D051096:Proto-Oncogene Proteins c-ret; D012333:RNA, Messenger; C065500:ASCL1 protein, human
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