Ontology highlight
ABSTRACT: Background
Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted.Methods
We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohort sets. Candidate loci were validated by target capture and Sanger sequencing. Gene set analysis was performed using Ingenuity Pathway Analysis.Results
We identified 27 genes potentially implicated in the pathogenesis of lung adenocarcinoma. These included targetable genes involved in PI3K/mTOR signaling (TSC1, PIK3CA, AKT2) and receptor tyrosine kinase signaling (ERBB4) and genes not previously highlighted in lung adenocarcinomas, such as SETD2 and PBRM1 (chromatin remodeling), CHEK2 and CDC27 (cell cycle), CUL3 and SOD2 (oxidative stress), and CSMD3 and TFG (immune response). In the expansion cohort (N = 70), TP53 was the most frequently altered gene (11%), followed by SETD2 (6%), CSMD3 (6%), ERBB2 (6%), and CDH10 (4%). In pathway analysis, the majority of altered genes were involved in cell cycle/DNA repair (P <0.001) and cAMP-dependent protein kinase signaling (P <0.001).Conclusions
The genomic makeup of EGFR/KRAS/ALK-negative lung adenocarcinomas in never-smokers is remarkably diverse. Genes involved in cell cycle regulation/DNA repair are implicated in tumorigenesis and represent potential therapeutic targets.
SUBMITTER: Ahn JW
PROVIDER: S-EPMC3979047 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Ahn Jin Woo JW Kim Han Sang HS Yoon Jung-Ki JK Jang Hoon H Han Soo Min SM Eun Sungho S Shim Hyo Sup HS Kim Hyun-Jung HJ Kim Dae Joon DJ Lee Jin Gu JG Lee Chang Young CY Bae Mi Kyung MK Chung Kyung Young KY Jung Ji Ye JY Kim Eun Young EY Kim Se Kyu SK Chang Joon J Kim Hye Ryun HR Kim Joo Hang JH Lee Min Goo MG Cho Byoung Chul BC Lee Ji Hyun JH Bang Duhee D
Genome medicine 20140227 2
<h4>Background</h4>Lung adenocarcinoma is a highly heterogeneous disease with various etiologies, prognoses, and responses to therapy. Although genome-scale characterization of lung adenocarcinoma has been performed, a comprehensive somatic mutation analysis of EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers has not been conducted.<h4>Methods</h4>We analyzed whole exome sequencing data from 16 EGFR/KRAS/ALK-negative lung adenocarcinomas and additional 54 tumors in two expansion cohor ...[more]