Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes.
OBJECTIVE
Aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer.


METHODS
We studied 51 candidate genes in 7 gastric cancer cell lines and 24 samples (training set) and identified 6 for further studies. We examined the methylation status of these genes in a test set consisting of 131 gastric neoplasias at various stages. Finally, we validated the 6 candidate genes in a different population of 40 primary gastric cancer samples and 113 nonneoplastic gastric mucosa samples.


RESULTS
Six genes (MINT25, RORA, GDNF, ADAM23, PRDM5, MLF1) showed frequent differential methylation between gastric cancer and normal mucosa in the training, test, and validation sets. GDNF and MINT25 were most sensitive molecular markers of early stage gastric cancer, whereas PRDM5 and MLF1 were markers of a field defect. There was a close correlation (r = 0.5-0.9, P = .03-.001) between methylation levels in tumor biopsy and gastric washes. MINT25 methylation had the best sensitivity (90%), specificity (96%), and area under the receiver operating characteristic curve (0.961) in terms of tumor detection in gastric washes.


CONCLUSIONS
These findings suggest MINT25 is a sensitive and specific marker for screening in gastric cancer. Additionally, we have developed a new method for gastric cancer detection by DNA methylation in gastric washes.
Watanabe
Yoshiyuki
Y
Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Kim
Hyun Soo
HS
Castoro
Ryan J
RJ
Chung
Woonbok
W
Estecio
Marcos R H
MR
Kondo
Kimie
K
Guo
Yi
Y
Ahmed
Saira S
SS
Toyota
Minoru
M
Itoh
Fumio
F
Suk
Ki Tae
KT
Cho
Mee-Yon
MY
Shen
Lanlan
L
Jelinek
Jaroslav
J
Issa
Jean-Pierre J
JP
D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000032:analysis; D055088:Early Detection of Cancer; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D011336:Probability; D012372:ROC Curve; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins