Promoter methylation and response to chemotherapy and radiation in esophageal cancer.
OBJECTIVE
Multiple studies have shown that promoter methylation of tumor suppressor genes underlies esophageal carcinogenesis. Hypothetically, methylation resulting in tumor suppressor gene inactivation might result in tumors that are unresponsive to chemotherapy and radiation. Accordingly, our aim was to find methylation markers that could be used to predict response to chemoradiation.


METHODS
Tumor specimens were obtained before treatment from 35 patients enrolled in a uniform chemoradiation treatment protocol. Methylation-specific quantitative polymerase chain reaction was performed on all samples. Pathology reports from esophagectomy specimens were used to define response to treatment.


RESULTS
Thirteen (37%) of 35 patients were responders, and 22 (63%) of 35 patients were nonresponders. The number of methylated genes per patient was significantly lower in responders than in nonresponders (1.4 vs 2.4 genes per patient; Student t test, P = .026). The combined mean level of promoter methylation of p16, Reprimo, p57, p73, RUNX-3, CHFR, MGMT, TIMP-3, and HPP1 was also lower in responders than in nonresponders (Student t test, P = .003; Mann-Whitney test, P = .001). The frequency (15% of responders vs 64% of nonresponders; Fisher exact test, P = .01) and level (0.078 in responders vs 0.313 in nonresponders; Mann-Whitney test, P = .037) of Reprimo methylation was significantly lower in responders than in nonresponders.


CONCLUSIONS
Reprimo methylation occurred at significantly lower levels and less frequently in chemoradioresponsive than in nonresponsive esophageal cancer patients, suggesting potential clinical application of this single-gene biomarker in defining prognosis and management. In addition, increased methylation of a 9-gene panel correlated significantly with poor responsiveness to chemoradiation.
Hamilton
James P
JP
Division of Gastroenterology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
Sato
Fumiaki
F
Greenwald
Bruce D
BD
Suntharalingam
Mohan
M
Krasna
Mark J
MJ
Edelman
Martin J
MJ
Doyle
Austin
A
Berki
Agnes T
AT
Abraham
John M
JM
Mori
Yuriko
Y
Kan
Takatsugu
T
Mantzur
Carmit
C
Paun
Bogdan
B
Wang
Suna
S
Ito
Tetsuo
T
Jin
Zhe
Z
Meltzer
Stephen J
SJ