Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4

Jenifer L. Marks, Michael McLellan, Maureen F. Zakowski, Alex E. Lash, Yumi Kasai, Stephen Broderick, Inderpal S. Sarkaria, Duy Khanh Pham, Bhuvanesh Singh, Tracie L. Miner, Ginger A. Fewell, Lucinda L. Fulton, Elaine R. Mardis, Richard K. Wilson, Mark G. Kris, Valerie W. Rusch, Harold Varmus, William Pao

Research output: Contribution to journalArticle

Abstract

Background. Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings. We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4(Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance. This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

Original languageEnglish (US)
Article numbere426
JournalPLoS One
Volume2
Issue number5
DOIs
StatePublished - May 9 2007
Externally publishedYes

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somatic mutation
adenocarcinoma
phosphotransferases (kinases)
Phosphotransferases
Genes
lungs
mutation
Mutation
Tumors
exons
neoplasms
genes
Exons
Dideoxynucleotides
Cells
major genes
lung neoplasms
carcinogenesis
Neoplasms
Ports and harbors

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. / Marks, Jenifer L.; McLellan, Michael; Zakowski, Maureen F.; Lash, Alex E.; Kasai, Yumi; Broderick, Stephen; Sarkaria, Inderpal S.; Pham, Duy Khanh; Singh, Bhuvanesh; Miner, Tracie L.; Fewell, Ginger A.; Fulton, Lucinda L.; Mardis, Elaine R.; Wilson, Richard K.; Kris, Mark G.; Rusch, Valerie W.; Varmus, Harold; Pao, William.

In: PLoS One, Vol. 2, No. 5, e426, 09.05.2007.

Research output: Contribution to journalArticle

Marks, JL, McLellan, M, Zakowski, MF, Lash, AE, Kasai, Y, Broderick, S, Sarkaria, IS, Pham, DK, Singh, B, Miner, TL, Fewell, GA, Fulton, LL, Mardis, ER, Wilson, RK, Kris, MG, Rusch, VW, Varmus, H & Pao, W 2007, 'Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4', PLoS One, vol. 2, no. 5, e426. https://doi.org/10.1371/journal.pone.0000426
Marks, Jenifer L. ; McLellan, Michael ; Zakowski, Maureen F. ; Lash, Alex E. ; Kasai, Yumi ; Broderick, Stephen ; Sarkaria, Inderpal S. ; Pham, Duy Khanh ; Singh, Bhuvanesh ; Miner, Tracie L. ; Fewell, Ginger A. ; Fulton, Lucinda L. ; Mardis, Elaine R. ; Wilson, Richard K. ; Kris, Mark G. ; Rusch, Valerie W. ; Varmus, Harold ; Pao, William. / Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4. In: PLoS One. 2007 ; Vol. 2, No. 5.
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abstract = "Background. Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings. We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4(Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance. This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.",
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T1 - Mutational analysis of EGFR and related signaling pathway genes in lung adenocarcinomas identifies a novel somatic kinase domain mutation in FGFR4

AU - Marks, Jenifer L.

AU - McLellan, Michael

AU - Zakowski, Maureen F.

AU - Lash, Alex E.

AU - Kasai, Yumi

AU - Broderick, Stephen

AU - Sarkaria, Inderpal S.

AU - Pham, Duy Khanh

AU - Singh, Bhuvanesh

AU - Miner, Tracie L.

AU - Fewell, Ginger A.

AU - Fulton, Lucinda L.

AU - Mardis, Elaine R.

AU - Wilson, Richard K.

AU - Kris, Mark G.

AU - Rusch, Valerie W.

AU - Varmus, Harold

AU - Pao, William

PY - 2007/5/9

Y1 - 2007/5/9

N2 - Background. Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings. We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4(Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance. This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

AB - Background. Fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode proteins in the EGFR signaling pathway, i.e., EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other potential somatic mutations in genes of this signaling pathway that could contribute to lung tumorigenesis. Methodology/Principal Findings. We analyzed genomic DNA from a total of 261 resected, clinically annotated non-small cell lung cancer (NSCLC) specimens. The coding sequences of 39 genes were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Sequencing of 9MB of tumor sequence identified 239 putative genetic variants. We further examined 22 variants found in RAS family genes and 135 variants localized to exons encoding the kinase domain of respective proteins. We identified a total of 37 non-synonymous somatic mutations; 36 were found collectively in EGFR, KRAS, BRAF, and PIK3CA. One somatic mutation was a previously unreported mutation in the kinase domain (exon 16) of FGFR4(Glu681Lys), identified in 1 of 158 tumors. The FGFR4 mutation is analogous to a reported tumor-specific somatic mutation in ERBB2 and is located in the same exon as a previously reported kinase domain mutation in FGFR4 (Pro712Thr) in a lung adenocarcinoma cell line. Conclusions/Significance. This study is one of the first comprehensive mutational analyses of major genes in a specific signaling pathway in a sizeable cohort of lung adenocarcinomas. Our results suggest the majority of gain-of-function mutations within kinase genes in the EGFR signaling pathway have already been identified. Our findings also implicate FGFR4 in the pathogenesis of a subset of lung adenocarcinomas.

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