Polymorphism of angiotensin I-converting enzyme gene is related to oral cancer and lymph node metastasis in male betel quid chewers
Introduction
Oral cancer is the most common malignancy observed in the head and neck area. In more than 90% of cases, oral cancer is characterized by oral squamous cell carcinoma (OSCC),1 and more than 90% of OSCCs develop from oral precancerous lesions (OPL) and oral precancerous conditions.2, 3 Areca nut/betel quid chewing as well as occupational and environmental exposures are the primary risk factors in oral cancer development.4, 5 However, many studies have shown that multiple genetic polymorphisms play roles in the development of OPL and oral cancer, implying that genetic factors, in combination with specific environmental factors, may predispose individuals to OPL and oral cancer.6, 7, 8
Angiotensin-converting enzyme (ACE) is expressed in a wide range of tissues,9, 10, 11, 12 and it converts angiotensin I to the potent vasoconstrictor, angiotensin II. Angiotensin II, the main peptide of the renin–angiotensin system, is strongly implicated in chronic inflammatory diseases such as hypertension, cardiovascular disease, and diabetes mellitus.13, 14, 15, 16 There is mounting evidence that ACE also participates locally in the pathology of carcinomas.17, 18 ACE is differentially expressed in several malignancies17 and influences tumor cell proliferation, migration, angiogenesis, and metastatic behavior.18, 19, 20 In humans, a polymorphism in the ACE gene—consisting of insertion (I) or deletion (D) of a 287-bp DNA fragment in intron 16—accounts for 20–50% of the variance in the expression of the ACE protein and its activity21, 22, 23, 24; the highest ACE levels were found in DD homozygotes, the lowest in II homozygotes, and intermediate values in heterozygotes.21 Furthermore, previous studies have shown that ACE is expressed locally in gastric cancer25, 26 and that I/D gene polymorphism influences metastatic behavior.27 Patients with the DD genotype had greater lymph node metastases and an advanced Union International Contre le Cancer (UICC) tumor stage than carriers of the ID or II genotype did.27 Another study found that ACE is differentially expressed in colorectal cancers and that gene polymorphism is associated with gender-specific differences in primary tumor size and patient survival.28 Our previous study also found that the ACE polymorphism increases the risk of OPL in a Taiwanese aboriginal population with a high prevalence of the betel quid chewing.29 On the basis of these observations, we aimed to further substantiate the influence of genetic polymorphisms of ACE on the susceptibility and clinicopathological development of oral cancer and the relationship between SNPs of the ACE gene with oral cancer risk and the clinicopathological characteristics.
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Patient populations and samples
Male patients with oral cancer (205) and 88 male patients with OPL were recruited from the Dental and Plastic Department of Kaohsiung Medical University and E-Da Hospital, I-Shou University, Taiwan between January 2003 and December 2010. Among patients with oral cancers, 15 showed veruccous carcinoma, four showed carcinoma in situ, and 186 showed OSCC. All patients were betel quid chewers. Oral cancer and OPL (including 19 persons with oral submucous fibrosis [OSF], 62 persons with oral
Results
All study subjects were male betel quid chewers. Patients with oral cancer had a significantly higher age and drinking duration, and lower cumulative quid consumption rate (50,000–100,000) than control subjects (Table 1). Furthermore, patients with OPL had a significantly higher age, rate of betel quid chewing accompanied with smoking, and drinking duration than control subjects. Moreover, compared to OPL patients, those with oral cancer had significantly higher rates of betel quid chewers with
Discussion
The present study shows that the ACE DD homozygote genotype is significantly more common in the betel quid chewing OPL and oral cancer patients than in the betel quid chewing control subjects. As determined by univariate and multivariate logistic regression analyses adjusted for age, smoking, drinking status, and betel chewing duration, the ACE DD homozygote genotype is independently associated with OPL and oral cancer. Additionally, oral cancer patients with the ACE DD homozygote genotype had
Conflict of interest
None declared.
Acknowledgments
The authors would like to thank the National Science Council and the E-Da Hospital of the Republic of China, Taiwan, for financially supporting this research under Contract Nos. NSC 98-2314-B-037-037-MY2, EDAHP-98007, and EDAHP99033.
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