Pathways Impacted by Genomic Alterations in Pulmonary Carcinoid Tumors
Autor: | Zhifu Sun, Farhad Kosari, Julian R. Molina, Dennis A. Wigle, Ping Yang, Sandra C. Schulte, Ray Kuang, Prasidda Khadka, Michael K. Asiedu, George Vasmatzis, Jie Dong, Jin Jen, Charles F. Thomas, Marie Christine Aubry |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine MAPK/ERK pathway Cancer Research Lung Neoplasms MAP Kinase Signaling System Carcinoid tumors Carcinoid Tumor Biology Pathogenesis 03 medical and health sciences 0302 clinical medicine Carcinoma medicine Humans Exome RNA Messenger Carcinoma Small Cell Lung Gene Exome sequencing Aged Amyloid beta-Peptides Cell Cycle NF-kappa B Genomics Middle Aged medicine.disease Small Cell Lung Carcinoma Carcinoma Neuroendocrine Neuroendocrine Tumors 030104 developmental biology Oncology 030220 oncology & carcinogenesis Mutation Cancer research RAD51C Female Mitogen-Activated Protein Kinases Signal Transduction |
Zdroj: | Clinical Cancer Research. 24:1691-1704 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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-κB 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. Clin Cancer Res; 24(7); 1691–704. ©2018 AACR. |
Databáze: | OpenAIRE |
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