Pathways impacted by genomic alterations in pulmonary carcinoid tumors

Michael K. Asiedu, Charles F. Thomas, Jie Dong, Sandra C. Schulte, Prasidda Khadka, Zhifu D Sun, Farhad Kosari, Jin Jen, Julian R Molina, George Vasmatzis, Ray Kuang, Marie Christine Aubry, Ping Yang, Dennis A Wigle

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-kB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

Original languageEnglish (US)
Pages (from-to)1691-1704
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018

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Carcinoid Tumor
Lung
Neoplasm Genes
Biological Phenomena
Exome
Neoplasms
Mutation
Neuroendocrine Tumors
MAP Kinase Signaling System
NF-kappa B
Amyloid beta-Protein Precursor
Small Cell Lung Carcinoma
Genes
Single Nucleotide Polymorphism
Cell Cycle
Cell Death
Research Design
Genome
Apoptosis
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Pathways impacted by genomic alterations in pulmonary carcinoid tumors. / Asiedu, Michael K.; Thomas, Charles F.; Dong, Jie; Schulte, Sandra C.; Khadka, Prasidda; Sun, Zhifu D; Kosari, Farhad; Jen, Jin; Molina, Julian R; Vasmatzis, George; Kuang, Ray; Aubry, Marie Christine; Yang, Ping; Wigle, Dennis A.

In: Clinical Cancer Research, Vol. 24, No. 7, 01.04.2018, p. 1691-1704.

Research output: Contribution to journalArticle

Asiedu, Michael K. ; Thomas, Charles F. ; Dong, Jie ; Schulte, Sandra C. ; Khadka, Prasidda ; Sun, Zhifu D ; Kosari, Farhad ; Jen, Jin ; Molina, Julian R ; Vasmatzis, George ; Kuang, Ray ; Aubry, Marie Christine ; Yang, Ping ; Wigle, Dennis A. / Pathways impacted by genomic alterations in pulmonary carcinoid tumors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 7. pp. 1691-1704.
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T1 - Pathways impacted by genomic alterations in pulmonary carcinoid tumors

AU - Asiedu, Michael K.

AU - Thomas, Charles F.

AU - Dong, Jie

AU - Schulte, Sandra C.

AU - Khadka, Prasidda

AU - Sun, Zhifu D

AU - Kosari, Farhad

AU - Jen, Jin

AU - Molina, Julian R

AU - Vasmatzis, George

AU - Kuang, Ray

AU - Aubry, Marie Christine

AU - Yang, Ping

AU - Wigle, Dennis A

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N2 - Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-kB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

AB - Purpose: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, comprise 30% of all carcinoid malignancies, and are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors. The role of specific genomic alterations in the pathogenesis of pulmonary carcinoid tumors remains poorly understood. We sought to identify genomic alterations and pathways that are deregulated in these tumors to find novel therapeutic targets for pulmonary carcinoid tumors. Experimental Design: We performed integrated genomic analysis of carcinoid tumors comprising whole genome and exome sequencing, mRNA expression profiling and SNP genotyping of specimens from normal lung, TC and AC, and small cell lung carcinoma (SCLC) to fully represent the lung neuroendocrine tumor spectrum. Results: Analysis of sequencing data found recurrent mutations in cancer genes including ATP1A2, CNNM1, MACF1, RAB38, NF1, RAD51C, TAF1L, EPHB2, POLR3B, and AGFG1. The mutated genes are involved in biological processes including cellular metabolism, cell division cycle, cell death, apoptosis, and immune regulation. The top most significantly mutated genes were TMEM41B, DEFB127, WDYHV1, and TBPL1. Pathway analysis of significantly mutated and cancer driver genes implicated MAPK/ERK and amyloid beta precursor protein (APP) pathways whereas analysis of CNV and gene expression data suggested deregulation of the NF-kB and MAPK/ERK pathways. The mutation signature was predominantly C>T and T>C transitions with a minor contribution of T>G transversions. Conclusions: This study identified mutated genes affecting cancer relevant pathways and biological processes that could provide opportunities for developing targeted therapies for pulmonary carcinoid tumors.

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