Ethnic differences and functional analysis of MET mutations in lung cancer

Soundararajan Krishnaswamy, Rajani Kanteti, Jonathan S. Duke-Cohan, Sivakumar Loganathan, Wanqing Liu, Patrick C. Ma, Martin Sattler, Patrick A. Singleton, Nithya Ramnath, Federico Innocenti, Dan L. Nicolae, Zheng Ouyang, Jie Liang, John Minna, Mark F. Kozloff, Mark K. Ferguson, Viswanathan Natarajan, Yi Ching Wang, Joe G N Garcia, Everett E. Vokes & 1 others Ravi Salgia

Research output: Contribution to journalArticle

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Abstract

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.

Original languageEnglish (US)
Pages (from-to)5714-5723
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number18
DOIs
StatePublished - Sep 15 2009

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Lung Neoplasms
Mutation
African Americans
Epidermal Growth Factor Receptor
Semaphorins
Hepatocyte Growth Factor
Ligands
Asian Americans
Proto-Oncogenes
Germ-Line Mutation
Mutation Rate
Protein-Tyrosine Kinases
Haplotypes
Squamous Cell Carcinoma
Exons
Neoplasms
Research Design
Genotype
Polymerase Chain Reaction
Lung

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Krishnaswamy, S., Kanteti, R., Duke-Cohan, J. S., Loganathan, S., Liu, W., Ma, P. C., ... Salgia, R. (2009). Ethnic differences and functional analysis of MET mutations in lung cancer. Clinical Cancer Research, 15(18), 5714-5723. https://doi.org/10.1158/1078-0432.CCR-09-0070

Ethnic differences and functional analysis of MET mutations in lung cancer. / Krishnaswamy, Soundararajan; Kanteti, Rajani; Duke-Cohan, Jonathan S.; Loganathan, Sivakumar; Liu, Wanqing; Ma, Patrick C.; Sattler, Martin; Singleton, Patrick A.; Ramnath, Nithya; Innocenti, Federico; Nicolae, Dan L.; Ouyang, Zheng; Liang, Jie; Minna, John; Kozloff, Mark F.; Ferguson, Mark K.; Natarajan, Viswanathan; Wang, Yi Ching; Garcia, Joe G N; Vokes, Everett E.; Salgia, Ravi.

In: Clinical Cancer Research, Vol. 15, No. 18, 15.09.2009, p. 5714-5723.

Research output: Contribution to journalArticle

Krishnaswamy, S, Kanteti, R, Duke-Cohan, JS, Loganathan, S, Liu, W, Ma, PC, Sattler, M, Singleton, PA, Ramnath, N, Innocenti, F, Nicolae, DL, Ouyang, Z, Liang, J, Minna, J, Kozloff, MF, Ferguson, MK, Natarajan, V, Wang, YC, Garcia, JGN, Vokes, EE & Salgia, R 2009, 'Ethnic differences and functional analysis of MET mutations in lung cancer', Clinical Cancer Research, vol. 15, no. 18, pp. 5714-5723. https://doi.org/10.1158/1078-0432.CCR-09-0070
Krishnaswamy S, Kanteti R, Duke-Cohan JS, Loganathan S, Liu W, Ma PC et al. Ethnic differences and functional analysis of MET mutations in lung cancer. Clinical Cancer Research. 2009 Sep 15;15(18):5714-5723. https://doi.org/10.1158/1078-0432.CCR-09-0070
Krishnaswamy, Soundararajan ; Kanteti, Rajani ; Duke-Cohan, Jonathan S. ; Loganathan, Sivakumar ; Liu, Wanqing ; Ma, Patrick C. ; Sattler, Martin ; Singleton, Patrick A. ; Ramnath, Nithya ; Innocenti, Federico ; Nicolae, Dan L. ; Ouyang, Zheng ; Liang, Jie ; Minna, John ; Kozloff, Mark F. ; Ferguson, Mark K. ; Natarajan, Viswanathan ; Wang, Yi Ching ; Garcia, Joe G N ; Vokes, Everett E. ; Salgia, Ravi. / Ethnic differences and functional analysis of MET mutations in lung cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 18. pp. 5714-5723.
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abstract = "Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13{\%} of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.",
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T1 - Ethnic differences and functional analysis of MET mutations in lung cancer

AU - Krishnaswamy, Soundararajan

AU - Kanteti, Rajani

AU - Duke-Cohan, Jonathan S.

AU - Loganathan, Sivakumar

AU - Liu, Wanqing

AU - Ma, Patrick C.

AU - Sattler, Martin

AU - Singleton, Patrick A.

AU - Ramnath, Nithya

AU - Innocenti, Federico

AU - Nicolae, Dan L.

AU - Ouyang, Zheng

AU - Liang, Jie

AU - Minna, John

AU - Kozloff, Mark F.

AU - Ferguson, Mark K.

AU - Natarajan, Viswanathan

AU - Wang, Yi Ching

AU - Garcia, Joe G N

AU - Vokes, Everett E.

AU - Salgia, Ravi

PY - 2009/9/15

Y1 - 2009/9/15

N2 - Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.

AB - Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.

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