Genetic association studies in digestive system malignancies.

The multifactorial process of carcinogenesis in the digestive system involves mutations in oncogenes or tumor suppressor genes, as well as influence of environmental etiological factors. In recent years, common DNA polymorphisms in low penetrance genes emerged as genetic factors that seem to modulate an individual's susceptibility to malignancy, through interaction with environmental factors, such as diet or smoking. The increasing number of publications of genetic association studies on digestive system neoplasias has produced both important true association results and negative or controversial results. Here, we review the findings of genetic association studies of gene polymorphisms in regard to cancers of the digestive tract (oral, esophageal, nasopharyngeal, gastric and colorectal). We discuss the association of several DNA polymorphisms in genes of cytokines, matrix metalloproteinases, signal transduction proteins, diet-, and coagulation-related factors with specific types of cancer in the digestive tract. Genetic studies, which lead to a true association, are expected to increase understanding of the pathogenesis of each malignancy and to be a powerful tool of prevention and prognosis in the future.

Diabetes increases both N-ras and ets-1 expression during rat oral oncogenesis resulting in enhanced cell proliferation and metastatic potential.

BACKGROUND: The expression of N-ras and ets-1 proteins was investigated in an experimental model of chemically-induced carcinogenesis in normal and diabetic (type I) Sprague-Dawley rats. MATERIALS AND METHODS: Tissue sections ranging from normal mucosa to moderately-differentiated oral squamous cell carcinoma were studied using monoclonal antibodies against N-ras and ets-1 proteins. RESULTS: In diabetic rats, N-ras expression increased with tumor advancement, while in normal rats N-ras was not detected in initial stages of oral oncogenesis and increased only in well-differentiated OSCC. The same pattern of elevated ets-1 expression was observed both in diabetic and normal rats, but in cancerous stages this expression was higher in diabetic than in normal rats. CONCLUSION: It seems that diabetes may contribute to increased cell proliferation due to N-ras constitutive activation, as well as to enhanced invasion and metastatic potential by increasing ets-1 levels.

Loss of tumour suppressor p16 expression in initial stages of oral oncogenesis.

BACKGROUND: The p16 tumour suppressor gene is known to be involved in regulation of the cell cycle. p16 expression in sequential histological stages of oral squamous cell carcinoma (OSCC) formation was investigated using an experimental model of induced oral carcinogenesis in Syrian golden hamsters. MATERIALS AND METHODS: Thirty-seven animals were divided into one control group (N = 7) and three experimental groups (N = 10 each) which were treated with a carcinogen and sacrificed at 10, 14 and 19 weeks after treatment. Tumour sections were studied immunohistochemically using monoclonal antibodies against p16 protein. RESULTS: p16 was found significantly increased in hyperplasia, sharply decreased in dysplasia and in the subsequent stages of oral carcinogenesis. CONCLUSION: Inactivation of p16 occurs at the early stage of oral mucosal dysplasia in the multistep process of oral tumourigenesis. Therefore, p16 may be considered as a useful prognostic marker for the progression of oral cancer.

Strong association of interleukin-4 (-590 C/T) polymorphism with increased risk for oral squamous cell carcinoma in Europeans.

OBJECTIVE: The present study was performed to investigate the possible association of -590 C/T polymorphism in the interleukin-4 (IL-4) gene which affects its expression with the risk for development of oral cancer. STUDY DESIGN: Polymerase chain reaction-based restriction analysis was performed in DNA samples of 156 patients with oral squamous cell carcinoma (OSCC) and 162 healthy control subjects of equivalent gender, age, and ethnicity (Greek and German). Statistical analyses were performed conducting Fisher exact test. RESULTS: The T/T genotype was associated with an increased risk for the development of OSCC (P = .018; OR 1.47, 95% CI 0.66-3.28), especially for early stages of this malignancy (P < .0001; OR 3.17, 95% CI 1.31-7.65). CONCLUSIONS: The above findings are consistent with the growth-promoting role of IL-4 in head and neck cancer and its inhibitory effect on neoangiogenesis and metastasis. The present study in Europeans is not in accordance with a previous report of unclear association of this polymorphism in a Chinese population.

Association of matrix metalloproteinase-1 (-1607 1G/2G) polymorphism with increased risk for oral squamous cell carcinoma.

BACKGROUND: The purpose of this study was to investigate the possible relation of matrix metalloproteinase-1 (MMP-1) to increased risk for oral cancer, in light of recently found contribution of angiogenesis and thrombosis-related factors to the development of malignancies. MATERIALS AND METHODS: The 1G/2G polymorphism in the MMP-1 gene, which influences its expression, was examined in 156 patients with oral squamous cell carcinoma and 141 healthy controls of comparable ethnicity (Greeks and Germans), gender and age. RESULTS: In comparison to controls, the detected 2G allele frequency was significantly lower in the patient group and in subgroups with early cancer stages, with positive family history of thrombophilia, with tobacco abuse and without alcohol abuse (p < 0.05). These findings were mainly due to a significant decrease in 2G/2G homozygotes despite a small increase in 1G/2G heterozygotes in the above groups. CONCLUSION: These findings suggest a significant involvement of the MMP-1 -1607 1G/2G polymorphism in the increasing risk for oral cancer in the 1G allele European carriers.

The (-590 C/T) polymorphism in the interleukin-4 gene is associated with increased risk for early stages of corolectal adenocarcinoma.

BACKGROUND: In the light of the known association between several carcinomas and the -590C/T polymorphism, which affects transcription of the antitumor interleukin-4 (IL-4) gene, the purpose of this study was to investigate the possible contribution of this polymorphism to the development of colorectal cancer. MATERIALS AND METHODS: The -590C/T polymorphism was examined in DNA samples of 93 patients with colorectal cancer (adenocarcinomas) and 108 healthy controls of comparable ethnicity, age and gender. RESULTS: The detected allele and carrier frequencies for the high expression T allele in the patient group were significantly decreased in comparison with that of the control group (13.44% versus 22.22%, and 21.51% versus 36.11%, respectively, p<0.01). The same pattern was observed between controls and patients in initial cancer stages. CONCLUSION: These findings indicate that IL-4 gene expression-related polymorphism is associated with the development of initial stages of colorectal cancer, while in advanced stages IL-4 levels appear to be less important.

No association with risk for colorectal cancer of the insertion/deletion polymorphism which affects levels of angiotensin-converting enzyme.

BACKGROUND: In the light of the established association of angiotensin-converting enzyme (ACE) with several types of cancer, the possible contribution of the insertion/deletion (I/D) polymorphism that affects ACE gene expression, in the development of colorectal cancer was investigated. MATERIALS AND METHODS: DNA samples of 92 patients with colorectal cancer (adenocarcinomas) and 102 healthy controls were examined by allele-specific polymerase chain reaction followed by electrophoretic analysis. The resulting allele and genotype frequencies of the patients were compared to those of the controls by Fischer's exact test and odds ratios. RESULTS: No statistical differences were observed between healthy controls and patients with colorectal cancer regarding either genotype distribution or low expression I allele frequency. CONCLUSION: The ACE I/D polymorphism is not a genetic predisposing factor concerning the risk for colorectal cancer.

Heterozygosity for interleukin-18 -607 A/C polymorphism is associated with risk for colorectal cancer.

BACKGROUND: The possible contribution of interleukin-18 (IL-18) -607 A/C polymorphism towards the development of colorectal cancer was investigated. PATIENTS AND METHODS: DNA samples of 84 patients with colorectal cancer (adenocarcinomas) and 89 healthy controls were examined by allele-specific polymerase chain reaction followed by electrophoretic analysis. The resulting allele and genotype frequencies of patients were compared to those of the respective controls using Fischer's exact test and odds ratios. RESULTS: The proportion of heterozygotes in the patient group was significantly higher than that in healthy controls (p < 0.01). This significant increase was detected independently of Dukes' tumor stage. Additionally, the carrier frequency of the mutant A allele was significantly higher in the patient group compared to controls (p < 0.05). CONCLUSION: The results indicate that heterozygotes for the IL-18 -607 A/C polymorphism exhibit increased risk for colorectal cancer development.