基因修補酵素XRCC1與hOGG1與食道癌關係之研究(2/2)
Date Issued
2004-07-31
Date
2004-07-31
Author(s)
李章銘
DOI
922314B002225
Abstract
The risk to develop esophageal cancer is associated with a variety of environmental and genetic
factors. Previously, we have found that individual susceptibility to esophageal cancer in Taiwan
was closely related to the consumption of tobacco, alcohol and areca. These factors exerted a
synergistic effect on the risk for esophageal cancer. On the other hand, the genetic variation was
also found important in determining the individual susceptibility to esophageal cancer. Genetic
polymorphisms of the xenobiotic metabolizing enzymes, GSTP1, GSTT1, and CYP1A1, tumor
suppressor gene, p53, or DNA repair enzymes, XRCC1 or hOGG1, can significantly influence the
risk of esophageal cancer. Given that the DNA damage is the common form induced by the environmental carcinogens and the main contributor to esophageal carcinogenesis, the individual
variation in the repairing capacity for damaged DNA would play a important role in determine the
tendency for individual carcinogenesis of the esophagus. Therefore, the aim of this study was to
investigate whether the genetic alteration of the DNA repair genes, hOGG1, and XRCC1 can modify
the individual risk to esophageal cancer. Previously, we have developed the technique of laser
capture microdissection (LCM) to obtain pure tumor DNA for analysis. Using this technique, we
have alleotyping the hOGG1 on intron 4 and exon 7, where the genetic polymorphisms locates. We
also genotyped the patients of esophageal cancer for the hOGG1 Ser 326 Cys genetic polymorphism
on intron 7. The expression of the hOGG1 in tumor was also examined by immunohistochemical
staining. Totally, we evaluated the status of LOH in tumor from 90 patients. Sixty-seven of them
further received immunohistochemical staining for the hOGG1 expression. 204 patients and 266
normal control received genotyping for the hOGG1 polymorphisms. We found that, the risk for the
esophageal cancer was enhanced by the presence of the hOGG1 326 Cys allele in the males who did
not regularly consume tobacco, alcohol, or areca nut, with ORs(95% CI) being 3.09 (1.22-7.81) for
the non-smokers, 2.40 (1.08-5.31) for the non-alcohol drinkers, and 1.86 (0.99-3.49) for the
non-areca chewers. Using the technique of Laser Capture Microdissection, we have alleotyping the
hOGG1 on intron 4 and exon 7, where the genetic polymorphisms locates. We also found the
allelic loss in genetic locus of hOGG1 is a very common episode with 62.2% of cases on the intron 4
and 56.7% of cases on the exon 7. The expression of the hOGG1 in the tumor tissue were also
reduced, with 82% of the patients having tumor without expressing or expressing only a very low
level of hOGG1 (less than 10% of the tumor cells).The pattern of protein expression and allelic
deletion of hOGG1 was not significantly affected by the individual exposure to tobacco, alcohol, or
areca nut. However, the deletion status intron 4 and exon 7 of hOGG1 can influence the survival of
esophageal cancer after treatment. Those patients who had LOH in the exon 7 of hogg1 have better
prognosis than the patients without LOH (p=0.06). This effect looked to be more evident in the
cigarette smokers (p<0.05), and alcohol drinkers (p<0.05). The status of lymphnode metastasis was
also associated with the deletion of hOGG1 in exon 7 (OR: 2.76; 95% CI: 1.03-7.38). On the
contrast, those patient without LOH in the intron 4 of hogg1 have better prognosis after surgery for
esophageal cancer (p=0.08). This effect was more prominent in the patients did not smoke cigarette
(p<0.05) or drink alcohol (p<0.05). This implies that repair of the oxidative damaged DNA,
8-oxoG, is not only an important mechanism for prevention of neoplasm in the esophagus but also
a significant factor affecting the tumor behaviour of esophageal cancer which might act with the
factor of environmental exposure.
Subjects
Esophageal cancer
Polymorphism
SDGs
Publisher
臺北市：國立臺灣大學醫學院外科
Type
report
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