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Exclusive mutation in epidermal growth factor receptor gene, HER‐2, and KRAS, and synchronous methylation of nonsmall cell lung cancer
Author(s) -
Suzuki Makoto,
Shigematsu Hisayuki,
Iizasa Toshihiko,
Hiroshima Kenzo,
Nakatani Yukio,
Minna John D.,
Gazdar Adi F.,
Fujisawa Takehiko
Publication year - 2006
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21853
Subject(s) - kras , methylation , cancer research , dna methylation , epidermal growth factor receptor , adenocarcinoma , epigenetics , biology , mutation , lung cancer , cancer , medicine , gene , oncology , genetics , gene expression
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 ≤.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 Ca 2+ ‐binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16 INK4A 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 p16 INK4A gene in NSCLC. Cancer 2006. © 2006 American Cancer Society.