High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer.
BACKGROUND
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.
*Departments of Solid Tumor Oncology; †Translational Hematology and Oncology Research, Cleveland Clinic Taussig Cancer Institute; ‡Case Comprehensive Cancer Center; §Departments of Molecular Pathology; and ‖Anatomic Pathology, Cleveland Clinic Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland, OH.
Yan
Y
Feng
Eugen C
EC
Minca
Christopher
C
Lanigan
Angen
A
Liu
Wei
W
Zhang
Lihong
L
Yin
Nathan A
NA
Pennell
Carol
C
Farver
Raymond
R
Tubbs
Patrick C
PC
Ma
D000328:Adult; D000368:Aged; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2; D000077547:Crizotinib; D005260:Female; D005784:Gene Amplification; D015321:Gene Rearrangement; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D008175:Lung Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis* / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics
D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases