Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer.
BACKGROUND
Both genetic and epigenetic changes in nonsmall cell lung cancer (NSCLC) are known to be a common event.


METHODS
Mutations in the epidermal growth factor receptor gene (EGFR), HER-2, and KRAS and the methylation profile of 9 genes for NSCLC were analyzed and correlated with clinical and histologic data.


RESULTS
Thirty-nine EGFR, 4 HER-2, and 6 KRAS mutations were found in 150 NSCLC cases, with the methylation percentages of the genes ranging from 13% to 54%. Most mutations were present in adenocarcinomas, but mutations of the 3 genes were never found to be present in individual tumors. The frequency of methylation for all the genes was correlated with the Methylation Index, a reflection of the overall methylation pattern (all genes, P< or = .01), supporting the presence of the CpG island methylator phenotype (CIMP) in NSCLC. On the basis of the methylation profile, CRBP1 and CDH13 methylation were good indicators of CIMP in NSCLC, and were correlated with a poorer prognosis in adenocarcinomas. Mutations in EGFR, HER-2, and KRAS were found to be present exclusively, whereas methylation tended to be present synchronously. A comparison of mutation and methylation demonstrated that the EGFR mutation had an inverse correlation with methylation of SPARC (secreted protein acidic and rich in cysteine), an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16INK4A gene.


CONCLUSIONS
The findings of the current study suggest that adenocarcinoma cases with CIMP have a poorer prognosis than adenocarcinoma cases without CIMP, and the EGFR mutation was shown to have an inverse correlation with methylation of SPARC and the p16INK4A gene in NSCLC.
Suzuki
Makoto
M
Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Inohana, Chiba, Japan. smakoto@faculty.chiba-u.jp
Shigematsu
Hisayuki
H
Iizasa
Toshihiko
T
Hiroshima
Kenzo
K
Nakatani
Yukio
Y
Minna
John D
JD
Gazdar
Adi F
AF
Fujisawa
Takehiko
T
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001707:Biopsy, Needle; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis
D014408:Biomarkers, Tumor