Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

Jin W. Ahn, Han S. Kim, Jung Ki Yoon, Hoon Jang, Soo M. Han, Sungho Eun, Hyo S. Shim, Hyun Jung Kim, Dae J. Kim, Jin G. Lee, Chang Y. Lee, Mi K. Bae, Kyung Y. Chung, Ji Y. Jung, Eun Y. Kim, Se K. Kim, Joon Chang, Hye R. Kim, Joo H. Kim, Min G. LeeByoung C. Cho, Ji H. Lee, Duhee Bang

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
Article number18
JournalGenome Medicine
Volume6
Issue number2
DOIs
Publication statusPublished - 2014 Feb 27

Fingerprint

Mutation
Genes
Cell Cycle
DNA Repair
Exome
Chromatin Assembly and Disassembly
Receptor Protein-Tyrosine Kinases
Cyclic AMP-Dependent Protein Kinases
Adenocarcinoma of lung
Phosphatidylinositol 3-Kinases
Carcinogenesis
Oxidative Stress
Genome
Therapeutics
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ahn, Jin W. ; Kim, Han S. ; Yoon, Jung Ki ; Jang, Hoon ; Han, Soo M. ; Eun, Sungho ; Shim, Hyo S. ; Kim, Hyun Jung ; Kim, Dae J. ; Lee, Jin G. ; Lee, Chang Y. ; Bae, Mi K. ; Chung, Kyung Y. ; Jung, Ji Y. ; Kim, Eun Y. ; Kim, Se K. ; Chang, Joon ; Kim, Hye R. ; Kim, Joo H. ; Lee, Min G. ; Cho, Byoung C. ; Lee, Ji H. ; Bang, Duhee. / Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers. In: Genome Medicine. 2014 ; Vol. 6, No. 2.
@article{fa0defadb68c454fb0db4cadccf5f26c,
title = "Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers",
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.",
author = "Ahn, {Jin W.} and Kim, {Han S.} and Yoon, {Jung Ki} and Hoon Jang and Han, {Soo M.} and Sungho Eun and Shim, {Hyo S.} and Kim, {Hyun Jung} and Kim, {Dae J.} and Lee, {Jin G.} and Lee, {Chang Y.} and Bae, {Mi K.} and Chung, {Kyung Y.} and Jung, {Ji Y.} and Kim, {Eun Y.} and Kim, {Se K.} and Joon Chang and Kim, {Hye R.} and Kim, {Joo H.} and Lee, {Min G.} and Cho, {Byoung C.} and Lee, {Ji H.} and Duhee Bang",
year = "2014",
month = "2",
day = "27",
doi = "10.1186/gm535",
language = "English",
volume = "6",
journal = "Genome Medicine",
issn = "1756-994X",
publisher = "BioMed Central",
number = "2",

}

Ahn, JW, Kim, HS, Yoon, JK, Jang, H, Han, SM, Eun, S, Shim, HS, Kim, HJ, Kim, DJ, Lee, JG, Lee, CY, Bae, MK, Chung, KY, Jung, JY, Kim, EY, Kim, SK, Chang, J, Kim, HR, Kim, JH, Lee, MG, Cho, BC, Lee, JH & Bang, D 2014, 'Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers', Genome Medicine, vol. 6, no. 2, 18. https://doi.org/10.1186/gm535

Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers. / Ahn, Jin W.; Kim, Han S.; Yoon, Jung Ki; Jang, Hoon; Han, Soo M.; Eun, Sungho; Shim, Hyo S.; Kim, Hyun Jung; Kim, Dae J.; Lee, Jin G.; Lee, Chang Y.; Bae, Mi K.; Chung, Kyung Y.; Jung, Ji Y.; Kim, Eun Y.; Kim, Se K.; Chang, Joon; Kim, Hye R.; Kim, Joo H.; Lee, Min G.; Cho, Byoung C.; Lee, Ji H.; Bang, Duhee.

In: Genome Medicine, Vol. 6, No. 2, 18, 27.02.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of somatic mutations in EGFR/KRAS/ALK-negative lung adenocarcinoma in never-smokers

AU - Ahn, Jin W.

AU - Kim, Han S.

AU - Yoon, Jung Ki

AU - Jang, Hoon

AU - Han, Soo M.

AU - Eun, Sungho

AU - Shim, Hyo S.

AU - Kim, Hyun Jung

AU - Kim, Dae J.

AU - Lee, Jin G.

AU - Lee, Chang Y.

AU - Bae, Mi K.

AU - Chung, Kyung Y.

AU - Jung, Ji Y.

AU - Kim, Eun Y.

AU - Kim, Se K.

AU - Chang, Joon

AU - Kim, Hye R.

AU - Kim, Joo H.

AU - Lee, Min G.

AU - Cho, Byoung C.

AU - Lee, Ji H.

AU - Bang, Duhee

PY - 2014/2/27

Y1 - 2014/2/27

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84898600834&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84898600834&partnerID=8YFLogxK

U2 - 10.1186/gm535

DO - 10.1186/gm535

M3 - Article

AN - SCOPUS:84898600834

VL - 6

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

IS - 2

M1 - 18

ER -