Abstract
Aberrant methylation of CpG islands acquired in promoter regions plays an important role in carcinogenesis. Accumulated evidence demonstrates FHIT gene promoter hyper-methylation is involved in non-small cell lung cancer (NSCLC). To test the diagnostic ability of FHIT methylation status on NSCLC, thirteen studies, including 2,119 samples were included in our meta-analysis. Simultaneously, four independent DNA methylation datasets from TCGA and GEO database were analyzed for validation. The pooled odds ratio of FHIT promoter methylation in cancer samples was 3.43 (95% CI: 1.85 to 6.36) compared with that in controls. In subgroup analysis, significant difference of FHIT gene promoter methylation status in NSCLC and controls was found in Asians but not in Caucasian population. In validation stage, 950 Caucasian samples, including 126 paired samples from TCGA, 568 cancer tissues and 256 normal controls from GEO database were analyzed, and all 8 CpG sites near the promoter region of FHIT gene were not significantly differentially methylated. Thus the diagnostic role of FHIT gene in the lung cancer may be relatively limited in the Caucasian population but useful in the Asians.
Highlights
Lung cancer is a complicated disease involving genetic and epigenetic variation, and is one of the leading causes of cancer death all over the world [1]
Lung cancer is often lacking of symptoms in its early stages, the five–year survival rate can be increased from 5% to 63% with the early stage of non-small cell lung cancer (NSCLC) showing the importance of early diagnosis of NSCLC [2, 3]
As for the study aim, 4 articles were especially aiming at NSCLC diagnosis, while the others were designed for the NSCLC prognosis or pathogenesis
Summary
Lung cancer is a complicated disease involving genetic and epigenetic variation, and is one of the leading causes of cancer death all over the world [1]. FHIT loss was observed in 64% of nonsmall-cell lung cancer patients and was significantly associated with squamous cell carcinoma and poor tumor www.impactjournals.com/oncotarget grade [10]. FHIT viral gene therapy was found to be able to prevent and reverse carcinogen-induced tumors in a gastric cancer mouse model [22]. FHIT is considered as a cancer suppressor gene and the loss or aberrant transcripts of FHIT may be associated with carcinogenesis. We performed a meta-analysis to evaluate the ability to use FHIT methylation level for early lung cancer diagnosis. We searched The Cancer Genome Atlas project (TCGA) as well as the Gene Expression Omnibus (GEO) database, collecting hundreds of NSCLC samples with whole genome DNA methylation datasets and comprehensive clinical information to validate our meta-analysis and correct for the publication bias [25].
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