DNA methylation markers and early recurrence in stage I lung cancer.
BACKGROUND
Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor.


METHODS
Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence.


RESULTS
In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC.


CONCLUSIONS
Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence.
Brock
Malcolm V
MV
Johns Hopkins Hospital, Baltimore, USA. mabrock@jhmi.edu
Hooker
Craig M
CM
Ota-Machida
Emi
E
Han
Yu
Y
Guo
Mingzhou
M
Ames
Stephen
S
Glöckner
Sabine
S
Piantadosi
Steven
S
Gabrielson
Edward
E
Pridham
Genevieve
G
Pelosky
Kristen
K
Belinsky
Steven A
SA
Yang
Stephen C
SC
Baylin
Stephen B
SB
Herman
James G
JG
D000368:Aged; D015820:Cadherins / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D019175:DNA Methylation; D005260:Female; D005500:Follow-Up Studies; D017491:Genes, APC; D016147:Genes, Tumor Suppressor; D019942:Genes, p16; D005819:Genetic Markers; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009367:Neoplasm Staging; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D015820:Cadherins; D005819:Genetic Markers; C099972:H-cadherin; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins