Identification of G0S2 as a gene frequently methylated in squamous lung cancer by combination of in silico and experimental approaches.
Epigenetic changes can lead to abnormal expression of genes in cancer, and several genes have been reported to have aberrant promoter DNA methylation in non-small-cell lung cancer (NSCLC). We identified aberrantly methylated genes in NSCLC by combination of in silico and experimental approaches. We first applied bioinformatics, and from microarray datasets, we selected genes with low expression and having functions related to cancer. Next, combined bisulfite restriction analysis was carried out in 10 pooled resected lung cancer tissues to screen for genes that were aberrantly methylated, and the methylation ratio (the fraction of methylated DNA in extracted DNA from a cancer tissue sample) was quantified using quantitative analysis of methylated alleles. We identified 8 methylated genes (ARPC1B, DNAH9, FLRT2, G0S2, IRS2, PKP1, SPOCK1 and UCHL1) previously unreported in NSCLC. Analyses of methylation profiles of 101 resected lung cancer tissue samples revealed quantitatively low methylation in whole, methylation ratios were almost less than 30% even in the methylated samples, and no significant correlation to prognosis after 2 years of follow-up using hierarchical clustering. DNA methylation of G0S2 gene was significantly more frequent in squamous lung cancer (n = 18, mean of methylation ratios: 15%) compared with nonsquamous lung cancer (n = 83, mean of methylation ratios: 2.6%) (Mann-Whitney U test, p < 0.001). DNA methylation of G0S2 can be an important biomarker for squamous lung cancer.
Kusakabe
Masashi
M
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Kutomi
Tomoko
T
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Watanabe
Kousuke
K
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Emoto
Noriko
N
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Aki
Naomi
N
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Kage
Hidenori
H
Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
Hamano
Emi
E
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Kitagawa
Hiroshi
H
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Nagase
Takahide
T
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Sano
Atsushi
A
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Yoshida
Yukihiro
Y
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Fukami
Takeshi
T
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Murakawa
Tomohiro
T
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Nakajima
Jun
J
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Takamoto
Shinichi
S
Department of General Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan.
Ota
Satoshi
S
Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan.
Fukayama
Masashi
M
Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan.
Yatomi
Yutaka
Y
Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
Ohishi
Nobuya
N
Department of Respiratory Medicine, The University of Tokyo Hospital, Tokyo, Japan.
Takai
Daiya
D
Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan.
D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C508073:G0S2 protein, human