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Cohypermethylation of p16 and FHIT Promoters as a Prognostic Factor of Recurrence in Surgically Resected Stage I Non–Small Cell Lung Cancer

¹ Center for Genome Research, Samsung Biomedical Research Institute; ² Seoul Science High School; Departments of ³ Pathology and ⁴ Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; and ⁵ Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea

Requests for reprints: Duk-Hwan Kim, Center for Genome Research, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Room B155, 50 Ilwon-dong, Kangnam-Ku, Seoul 135-710, Republic of Korea. Phone: 82-23410-3632; Fax: 82-23410-3649; E-mail: dukhwan.kim{at}samsung.com.

Despite advances in the detection and treatment of lung cancer, the prognosis for patients with lung cancer is poor, partly as a result of recurrences. We retrospectively analyzed the relationship between recurrence and survival in patients with non–small cell lung cancers (NSCLC), and the promoter methylation of p16, GSTP1, FHIT, H-cadherin, and RARß2 genes to identify a prognostic molecular marker associated with the recurrence of NSCLC. Methylation status from 335 paraffin blocks was determined by methylation-specific PCR. Of the 335 NSCLC samples, promoter methylation was detected in 35% for p16, 39% for RARß2, 42% for H-cadherin, 7% for GSTP1, and 21% for FHIT. Recurrence was observed in 39% (132 of 335) of the patients. Recurrence was significantly associated with histology (P = 0.001) and pathologic stage (P = 0.009). Hypermethylation of any single gene was not associated with recurrence in patients. However, cohypermethylation of p16 and FHIT genes in stage I NSCLCs was associated with an increased risk of recurrence [odds ratio, 6.43; 95% confidence interval (CI), 1.04-20.19; P = 0.02] and poor recurrence-free survival after surgery (hazard ratio, 2.03; 95% CI, 1.09-6.23; P = 0.02). In addition, their survival after recurrence was also 4.62 times poorer (95% CI, 1.27-16.48; P = 0.005) than for those without cohypermethylation of both genes. In conclusion, the present study suggests that cohypermethylation of p16 and FHIT genes in patients with stage I NSCLC may be a valuable biomarker for predicting the recurrence-associated prognosis of the disease. (Cancer Res 2006; 66(8): 4049-54)

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