ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation

Farhad Kosari, C. M. Ida, M. C. Aubry, L. Yang, Irina V Kovtun, J. L S Klein, Y. Li, S. Erdogan, S. C. Tomaszek, S. J. Murphy, L. C. Bolette, C. P. Kolbert, Ping Yang, Dennis A Wigle, George Vasmatzis

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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.

Original languageEnglish (US)
Pages (from-to)3776-3783
Number of pages8
JournalOncogene
Volume33
Issue number29
DOIs
StatePublished - Jul 17 2014

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Adenocarcinoma
Oncogenes
Lung Neoplasms
Biomarkers
Chromogranins
Neural Cell Adhesion Molecules
Neoplasms
Neuroendocrine Cells
Synaptophysin
Transcriptome
Computer Simulation
Small Interfering RNA
Cell Movement
Proteins
Transcription Factors
Smoking
Adenocarcinoma of lung
Lung
Messenger RNA
Growth

Keywords

  • lung cancer
  • MASH1
  • microarray
  • neuroendocrine
  • prognostic biomarker

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. / Kosari, Farhad; Ida, C. M.; Aubry, M. C.; Yang, L.; Kovtun, Irina V; Klein, J. L S; Li, Y.; Erdogan, S.; Tomaszek, S. C.; Murphy, S. J.; Bolette, L. C.; Kolbert, C. P.; Yang, Ping; Wigle, Dennis A; Vasmatzis, George.

In: Oncogene, Vol. 33, No. 29, 17.07.2014, p. 3776-3783.

Research output: Contribution to journalArticle

Kosari, F, Ida, CM, Aubry, MC, Yang, L, Kovtun, IV, Klein, JLS, Li, Y, Erdogan, S, Tomaszek, SC, Murphy, SJ, Bolette, LC, Kolbert, CP, Yang, P, Wigle, DA & Vasmatzis, G 2014, 'ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation', Oncogene, vol. 33, no. 29, pp. 3776-3783. https://doi.org/10.1038/onc.2013.359
Kosari, Farhad ; Ida, C. M. ; Aubry, M. C. ; Yang, L. ; Kovtun, Irina V ; Klein, J. L S ; Li, Y. ; Erdogan, S. ; Tomaszek, S. C. ; Murphy, S. J. ; Bolette, L. C. ; Kolbert, C. P. ; Yang, Ping ; Wigle, Dennis A ; Vasmatzis, George. / ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. In: Oncogene. 2014 ; Vol. 33, No. 29. pp. 3776-3783.
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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.",
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T1 - ASCL1 and RET expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation

AU - Kosari, Farhad

AU - Ida, C. M.

AU - Aubry, M. C.

AU - Yang, L.

AU - Kovtun, Irina V

AU - Klein, J. L S

AU - Li, Y.

AU - Erdogan, S.

AU - Tomaszek, S. C.

AU - Murphy, S. J.

AU - Bolette, L. C.

AU - Kolbert, C. P.

AU - Yang, Ping

AU - Wigle, Dennis A

AU - Vasmatzis, George

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N2 - 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.

AB - 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.

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