Long interspersed nuclear element 1 hypomethylation is a marker of poor prognosis in stage IA non-small cell lung cancer.
OBJECTIVE
Global hypomethylation and the hypermethylation of gene promoter regions are common events in tumor DNA. The aim of this study was to evaluate the prognostic significance of both global hypomethylation and gene promoter hypermethylation in DNA from non-small cell lung cancer (NSCLC).


METHODS
Genomic DNA was obtained from the tumor tissue of 379 NSCLC patients who underwent surgery. Methylation levels were measured by real-time PCR following bisulfite modification of DNA and were correlated with clinicopathologic parameters and patient prognosis. Methylation of long interspersed nuclear element 1 (LINE-1) was used as a surrogate marker for global methylation. Hypermethylation of the APC, CDH13, and RASSF1 promoter regions was also evaluated.


RESULTS
Tumor tissue showed significantly higher CDH13 and RASSF1 methylation levels compared with normal lung tissue, but lower LINE-1 methylation levels. APC, RASSF1, and LINE-1 methylation levels were significant prognostic factors in univariate analysis of an initial cohort of 234 cases. APC and LINE-1 methylation remained significant prognostic factors in multivariate analysis that included age, gender, smoking history, histologic type, and pathologic stage. LINE-1 methylation showed marginally significant prognostic value in stage IA and IB disease. Expansion of the study cohort to 364 cases revealed that LINE-1 methylation had significant prognostic value for stage IA NSCLC patients in multivariate analysis.


CONCLUSIONS
LINE-1 hypomethylation was an independent marker of poor prognosis in stage IA NSCLC. Validation of this finding in additional tumor cohorts could have clinical relevance for the management of early-stage NSCLC.
Saito
Kenichiro
K
Division of Translational and Clinical Oncology, Molecular and Cellular Targeting Translational Oncology Center, Cancer Research Institute, Kanazawa University, Japan.
Kawakami
Kazuyuki
K
Matsumoto
Isao
I
Oda
Makoto
M
Watanabe
Go
G
Minamoto
Toshinari
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics*; D015331:Cohort Studies; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D017491:Genes, APC / Q000502:physiology; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics*; D019656:Loss of Heterozygosity; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
D015820:Cadherins; C099972:H-cadherin; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D004247:DNA