High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer

Yan Feng, Eugen C. Minca, Christopher Lanigan, Angen Liu, Wei Zhang, Lihong Yin, Nathan A. Pennell, Carol Farver, Raymond Tubbs, Patrick C. Ma

Research output: Contribution to journalArticle

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Abstract

INTRODUCTION:: Overexpression of MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) and MET gene amplification have been well-documented in non-small-cell lung cancer (NSCLC). Activated MET signaling plays an important role in human cancer tumorigenesis, metastasis, and drug resistance. However, the deregulation of MET/HGF pathway in NSCLC harboring ALK gene rearrangement (ALK[+]), which is sensitive to dual ALK and MET inhibitor Crizotinib, has not been reported. METHODS:: We performed systematic analysis of MET/HGF expression by immunohistochemistry (IHC) and MET gene amplification by dual color, dual hapten bright field in situ hybridization in 19 ALK(+) and 73 ALK(-) NSCLC tumor tissues from those who had clinical ALK rearrangement test done at the Cleveland Clinic from August 2010 to January 2013. IHC scoring was interpreted on a standard four-tier system. RESULTS:: The percentage of MET IHC score 0, 1+, 2+, and 3+ were 5.5%, 27.8%, 50.0%, and 16.7% in ALK(+) group, compared with 28.8%, 33.9%, 23.7%, and 13.6% in ALK(-) group, respectively. The MET high expression (IHC score 2 or 3) was significantly higher in ALK(+) group statistically (66.7% versus 37.3%, p = 0.03). HGF-high expression (IHC score 2 or 3) was 33.3% in ALK(+) and 15.8% in ALK(-) (p = 0.17). We identified eight cases in ALK(-) and one case in ALK(+) tumor who had MET gene amplification (18.4% versus 7.1%, p = 0.43) by dual color, dual hapten bright field in situ hybridization. No significant correlation between MET protein receptor expression and gene amplification was identified. CONCLUSIONS:: Our study demonstrated for the first time that MET receptor expression, but not MET gene amplification, is significantly increased in ALK(+) NSCLC. MET gene amplification is a relatively rare event in this unique population compared with ALK(-) NSCLC.

Original languageEnglish (US)
Pages (from-to)646-653
Number of pages8
JournalJournal of Thoracic Oncology
Volume9
Issue number5
DOIs
StatePublished - May 2014

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Gene Amplification
Non-Small Cell Lung Carcinoma
Hepatocyte Growth Factor
Immunohistochemistry
Haptens
In Situ Hybridization
Color
Proto-Oncogene Proteins c-met
Neoplasms
Gene Rearrangement
Drug Resistance
Carcinogenesis
Neoplasm Metastasis
Ligands
Population
Proteins

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Feng, Yan ; Minca, Eugen C. ; Lanigan, Christopher ; Liu, Angen ; Zhang, Wei ; Yin, Lihong ; Pennell, Nathan A. ; Farver, Carol ; Tubbs, Raymond ; Ma, Patrick C. / High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer. In: Journal of Thoracic Oncology. 2014 ; Vol. 9, No. 5. pp. 646-653.
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abstract = "INTRODUCTION:: Overexpression of MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) and MET gene amplification have been well-documented in non-small-cell lung cancer (NSCLC). Activated MET signaling plays an important role in human cancer tumorigenesis, metastasis, and drug resistance. However, the deregulation of MET/HGF pathway in NSCLC harboring ALK gene rearrangement (ALK[+]), which is sensitive to dual ALK and MET inhibitor Crizotinib, has not been reported. METHODS:: We performed systematic analysis of MET/HGF expression by immunohistochemistry (IHC) and MET gene amplification by dual color, dual hapten bright field in situ hybridization in 19 ALK(+) and 73 ALK(-) NSCLC tumor tissues from those who had clinical ALK rearrangement test done at the Cleveland Clinic from August 2010 to January 2013. IHC scoring was interpreted on a standard four-tier system. RESULTS:: The percentage of MET IHC score 0, 1+, 2+, and 3+ were 5.5{\%}, 27.8{\%}, 50.0{\%}, and 16.7{\%} in ALK(+) group, compared with 28.8{\%}, 33.9{\%}, 23.7{\%}, and 13.6{\%} in ALK(-) group, respectively. The MET high expression (IHC score 2 or 3) was significantly higher in ALK(+) group statistically (66.7{\%} versus 37.3{\%}, p = 0.03). HGF-high expression (IHC score 2 or 3) was 33.3{\%} in ALK(+) and 15.8{\%} in ALK(-) (p = 0.17). We identified eight cases in ALK(-) and one case in ALK(+) tumor who had MET gene amplification (18.4{\%} versus 7.1{\%}, p = 0.43) by dual color, dual hapten bright field in situ hybridization. No significant correlation between MET protein receptor expression and gene amplification was identified. CONCLUSIONS:: Our study demonstrated for the first time that MET receptor expression, but not MET gene amplification, is significantly increased in ALK(+) NSCLC. MET gene amplification is a relatively rare event in this unique population compared with ALK(-) NSCLC.",
author = "Yan Feng and Minca, {Eugen C.} and Christopher Lanigan and Angen Liu and Wei Zhang and Lihong Yin and Pennell, {Nathan A.} and Carol Farver and Raymond Tubbs and Ma, {Patrick C.}",
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High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer. / Feng, Yan; Minca, Eugen C.; Lanigan, Christopher; Liu, Angen; Zhang, Wei; Yin, Lihong; Pennell, Nathan A.; Farver, Carol; Tubbs, Raymond; Ma, Patrick C.

In: Journal of Thoracic Oncology, Vol. 9, No. 5, 05.2014, p. 646-653.

Research output: Contribution to journalArticle

TY - JOUR

T1 - High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer

AU - Feng, Yan

AU - Minca, Eugen C.

AU - Lanigan, Christopher

AU - Liu, Angen

AU - Zhang, Wei

AU - Yin, Lihong

AU - Pennell, Nathan A.

AU - Farver, Carol

AU - Tubbs, Raymond

AU - Ma, Patrick C.

PY - 2014/5

Y1 - 2014/5

N2 - INTRODUCTION:: Overexpression of MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) and MET gene amplification have been well-documented in non-small-cell lung cancer (NSCLC). Activated MET signaling plays an important role in human cancer tumorigenesis, metastasis, and drug resistance. However, the deregulation of MET/HGF pathway in NSCLC harboring ALK gene rearrangement (ALK[+]), which is sensitive to dual ALK and MET inhibitor Crizotinib, has not been reported. METHODS:: We performed systematic analysis of MET/HGF expression by immunohistochemistry (IHC) and MET gene amplification by dual color, dual hapten bright field in situ hybridization in 19 ALK(+) and 73 ALK(-) NSCLC tumor tissues from those who had clinical ALK rearrangement test done at the Cleveland Clinic from August 2010 to January 2013. IHC scoring was interpreted on a standard four-tier system. RESULTS:: The percentage of MET IHC score 0, 1+, 2+, and 3+ were 5.5%, 27.8%, 50.0%, and 16.7% in ALK(+) group, compared with 28.8%, 33.9%, 23.7%, and 13.6% in ALK(-) group, respectively. The MET high expression (IHC score 2 or 3) was significantly higher in ALK(+) group statistically (66.7% versus 37.3%, p = 0.03). HGF-high expression (IHC score 2 or 3) was 33.3% in ALK(+) and 15.8% in ALK(-) (p = 0.17). We identified eight cases in ALK(-) and one case in ALK(+) tumor who had MET gene amplification (18.4% versus 7.1%, p = 0.43) by dual color, dual hapten bright field in situ hybridization. No significant correlation between MET protein receptor expression and gene amplification was identified. CONCLUSIONS:: Our study demonstrated for the first time that MET receptor expression, but not MET gene amplification, is significantly increased in ALK(+) NSCLC. MET gene amplification is a relatively rare event in this unique population compared with ALK(-) NSCLC.

AB - INTRODUCTION:: Overexpression of MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) and MET gene amplification have been well-documented in non-small-cell lung cancer (NSCLC). Activated MET signaling plays an important role in human cancer tumorigenesis, metastasis, and drug resistance. However, the deregulation of MET/HGF pathway in NSCLC harboring ALK gene rearrangement (ALK[+]), which is sensitive to dual ALK and MET inhibitor Crizotinib, has not been reported. METHODS:: We performed systematic analysis of MET/HGF expression by immunohistochemistry (IHC) and MET gene amplification by dual color, dual hapten bright field in situ hybridization in 19 ALK(+) and 73 ALK(-) NSCLC tumor tissues from those who had clinical ALK rearrangement test done at the Cleveland Clinic from August 2010 to January 2013. IHC scoring was interpreted on a standard four-tier system. RESULTS:: The percentage of MET IHC score 0, 1+, 2+, and 3+ were 5.5%, 27.8%, 50.0%, and 16.7% in ALK(+) group, compared with 28.8%, 33.9%, 23.7%, and 13.6% in ALK(-) group, respectively. The MET high expression (IHC score 2 or 3) was significantly higher in ALK(+) group statistically (66.7% versus 37.3%, p = 0.03). HGF-high expression (IHC score 2 or 3) was 33.3% in ALK(+) and 15.8% in ALK(-) (p = 0.17). We identified eight cases in ALK(-) and one case in ALK(+) tumor who had MET gene amplification (18.4% versus 7.1%, p = 0.43) by dual color, dual hapten bright field in situ hybridization. No significant correlation between MET protein receptor expression and gene amplification was identified. CONCLUSIONS:: Our study demonstrated for the first time that MET receptor expression, but not MET gene amplification, is significantly increased in ALK(+) NSCLC. MET gene amplification is a relatively rare event in this unique population compared with ALK(-) NSCLC.

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