Hypermethylation of FHIT as a prognostic marker in nonsmall cell lung carcinoma.
BACKGROUND
Methylation of CpG islands in the promoter and upstream coding regions has been identified as a mechanism for transcriptional inactivation of tumor suppressor genes. The purpose of the current study was to determine the correlation between the aberrant promoter methylation of multiple genes and survival in patients with nonsmall cell lung carcinoma (NSCLC).


METHODS
The methylation status of nine genes was determined in 124 surgically resected NSCLC cases using methylation-specific polymerase chain reaction.


RESULTS
The methylation frequencies of the genes tested in NSCLC specimens were 52% for E-cadherin (CDH1), 41% for RAS association domain family protein (RASSF1A), 38% for fragile histidine triad (FHIT) and adenomatous polyposis coli (APC), 27% for retinoic acid receptor beta (RARbeta) and H-cadherin (CDH13), 20% for p16INK4A, 0.8% for O6-methylguanine-DNA-methyltransferase (MGMT), and 0% for glutathione S-transferase P1 (GSTP1). The survival of the patients with FHIT methylation-positive tumors was found to be significantly shorter than that for those patients with methylation-negative tumors (P=0.03), even in those patients with International Union Against Cancer TNM Stage I or Stage II disease (P=0.007). In contrast, there were no significant survival differences noted between the methylation-positive and methylation-negative tumors for the other genes tested. In addition, based on multivariate analyses, FHIT methylation-positive status was found to be independently associated with poor survival (P=0.046) and disease stage (P<0.0001).


CONCLUSIONS
The results of the current study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC.
Maruyama
Riichiroh
R
Hamon Center for Therapeutic Oncology Research, the University of Texas Southwestern Medical Center, Dallas, Texas, USA. rmaruyama@nk-cc.go.jp
Sugio
Kenji
K
Yoshino
Ichiro
I
Maehara
Yoshihiko
Y
Gazdar
Adi F
AF
D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase