Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status.
BACKGROUND
The mutation and amplification of oncogenic genes are associated with carcinogenesis and tumor growth. The purpose of this study was to clarify the role of the epidermal growth factor receptor (EGFR), K-ras, MET, and hepatocyte growth factor (HGF) status in lung adenocarcinoma.


METHODS
Tumor specimens were collected from 183 patients who underwent a complete resection for adenocarcinoma of the lung from 2003 to 2007 in our department. The genetic status of the EGFR and K-ras genes were investigated by polymerase chain reaction (PCR)-based analyses. Immunohistochemistry and real time PCR assays were used to evaluate the MET gene regarding to tyrosine phosphorylation and amplification, respectively. HGF status was evaluated by immunohistochemistry.


RESULTS
The mutations of EGFR and K-ras were detected in 64 (35%) and 17 patients (9%), respectively. The tyrosine 1234/1235 phosphorylation of MET (p-MET 1234/1235) and MET amplification was identified in 12 (7%) and 8 (4%) specimens, respectively. Positive expression of HGF was identified in 104 specimens (57%). An EGFR mutation was found significantly more frequently in females and in tumors with wild type of K-ras and without MET amplification. A p-MET 1234/1235 was found significantly more frequently in the tumors with a positive expression of HGF. A multivariate survival analysis demonstrated that the wild type of K-ras, negative p-MET 1234/1235, and positive HGF expression were independently associated with an increased risk of poor survival.


CONCLUSIONS
The occurrence of MET amplification and EGFR/ K-ras mutations might be mutually exclusive suggesting several distinct mechanisms in the development of lung adenocarcinoma. The wild type of K-ras, negative p-MET 1234/1235, and positive expression of HGF may be a useful marker for predicting poor prognosis of patients who underwent surgical resection of lung adenocarcinoma.
Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan.
Takamitsu
T
Onitsuka
Hidetaka
H
Uramoto
Kenji
K
Ono
Mitsuhiro
M
Takenoyama
Takeshi
T
Hanagiri
Tsunehiro
T
Oyama
Hiroto
H
Izumi
Kimitoshi
K
Kohno
Kosei
K
Yasumoto
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004273:DNA, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
D004273:DNA, Neoplasm; C066855:HGF protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins