Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma.
We examined the genome-wide expression profiles of 86 primary lung adenocarcinomas and compared them with the mutation status of the four key molecules (EGFR, ERBB2, KRAS and BRAF) in the EGFR/KRAS/BRAF pathway. Unsupervised classification revealed two subtypes (the bronchial type and the alveolar type) of lung adenocarcinoma. Mutually exclusive somatic mutations of the epidermal growth factor receptor (EGFR) gene (36/86, 41.8%), K-ras gene (11/86, 12.8%) and BRAF gene (1/86, 1.1%) were detected. KRAS mutations were observed significantly frequently in bronchial-type tumors, whereas the frequencies of EGFR mutations were similar in both the alveolar and bronchial types. Twenty-seven genes showed increased expression in EGFR-mutated tumors and these included molecules that function in the EGFR/KRAS/BRAF pathway (EGFR, AKT1 and BCR). In particular, expression of BCR, which is required for EGFR protein degradation, was induced by EGF stimulation, suggesting a negative feedback loop in lung cancer. A subgroup of the alveolar type tumors showed significantly better prognosis than other tumors. Integrated analysis of genetic and gene expression profiling aimed to delineate inherent oncogenic pathways in cancer will be valuable not only for the understanding of molecular pathogenesis, but also for discovering novel biomarkers and predicting clinical outcome.
Shibata
Tatsuhiro
T
Cancer Genomics Project, Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. tashibat@ncc.go.jp
Hanada
Satoko
S
Kokubu
Akiko
A
Matsuno
Yoshihiro
Y
Asamura
Hisao
H
Ohta
Tsutomu
T
Sakamoto
Michiie
M
Hirohashi
Setsuo
S
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D009154:Mutation; D009367:Neoplasm Staging; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics*
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins