Promoter hypermethylation of RASSF1A and RUNX3 genes as an independent prognostic prediction marker in surgically resected non-small cell lung cancers.
Aberrant methylation of promoter CpG islands is known to be a major inactivation mechanism of the tumor suppressor and tumor-related genes. Some published studies suggest a relationship to exist between the methylation status of several genes and the prognosis in non-small cell lung cancer (NSCLC); hypermethylation of the specific genes may be expected to serve as a biomarker for the prognosis, after a curative resection of NSCLC. To determine the relationship between the methylation status of the tumor suppressor and the tumor-related genes, and the clinicopathologic characteristics, including the survival rate, in patients with NSCLC after a surgical resection, we studied methylation in 10 genes (DAPK, FHIT, H-cadherin, MGMT, p14, p16, RAR-beta, RASSF1A, RUNX3, and TIMP-3) in 101 NSCLC cases by methylation-specific PCR (MSP). The methylation frequencies of the 10 genes examined in NSCLC were 26% for DAPK, 34% for FHIT, 26% for H-cadherin, 14% for MGMT, 8% for p14, 27% for p16, 38% for RAR-beta, 42% for RASSF1A, 25% for RUNX3, and 12% for TIMP-3. Clinicopathologically, the patients with all stages of disease who had positive RASSF1A, RUNX3, or H-cadherin methylation status were found to have a significantly shorter duration of survival, as compared with the patients with a negative methylation status for those genes (RASSF1A:P=0.023, RUNX3:P=0.035, H-cadherin:P=0.039) in univariate analysis. Thereafter, while limiting our examination to patients with stage I disease, the patients who had a positive RASSF1A or RUNX3 methylation status were found to have a significantly shorter duration of survival, in comparison to the patients with negative methyaltion status for each of those genes (RASSF1A:P=0.022, RUNX3:P<0.01) in univariate analysis. Next, the histological differences were recognized that the patients with RUNX3 methylation had a shorter duration of survival in adenocarcinomas (ACs) (P=0.045), in contrast to those with RASSF1A methylation who had a shorter duration of survival in squamous cell carcinomas (SCCs) (P=0.021). In multivariate analysis, both positive RASSF1A methylation status, and positive RUNX3 methylation status were found to be independent prognostic factors (RASSF1A:P=0.031, RUNX3:P=0.028), as was TNM stage (P=0.004) and pleural involvement (P=0.037). In conclusion, the hypermethylation of RASSF1A or RUNX3 gene is therefore a useful biomarker to predict the prognosis in NSCLC, particularly RASSF1A due to SCCs and RUNX3 due to ACs.
Yanagawa
Naoki
N
Department of Pathology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan. nyanagaw@med.id.yamagata-u.ac.jp
Tamura
Gen
G
Oizumi
Hiroyuki
H
Kanauchi
Naoki
N
Endoh
Makoto
M
Sadahiro
Mitsuaki
M
Motoyama
Teiichi
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D052138:Genes, Neoplasm; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D015820:Cadherins; D050677:Core Binding Factor Alpha 3 Subunit; D005819:Genetic Markers; C099972:H-cadherin; C411762:RASSF1 protein, human; C493729:Runx3 protein, human; D025521:Tumor Suppressor Proteins