Upper Gastrointestinal Tumors

Gene Polymorphism in Esophageal Squamous-Cell Cancer

In the developed countries, a causal relationship has been strongly established between esophageal squamous-cell cancer and consumption of alcohol (classified as a nutrient) and tobacco (classified as carcinogen-generating nitrosamines). Chronic inflammation of the mucosa (esophagitis) has been regarded as a preneoplastic condition in these patients. However, the predisposition to develop cancer is influenced by genetic polymorphism - i. e., the variable ability of individuals to metabolize toxic or carcinogenic agents.

Muto et al. [1] assessed the risk of multiple head and neck cancers (in the hypopharynx, oropharynx, oral cavity, and larynx) in 203 patients with newly diagnosed squamous-cell carcinoma. A total of 163 patients had a solitary cancer, while 40 had multiple cancers. The patients’ drinking and smoking habits were noted. Lugol chromoendoscopy was used to assess the topography of unstained epithelial areas. Genetic polymorphisms for the metabolism of ethanol were identified using polymerase chain reaction (PCR) for the allele of the ADH3-2 variant of alcohol dehydrogenase (ADH), resulting in slow metabolism of ethanol with progressive transformation into acetaldehyde; and for the deficiency variant ALDH2 of aldehyde dehydrogenase (ALDH), responsible for the accumulation of acetaldehyde. Multiple Lugol-negative areas in the esophagus, found only in smoking drinkers, were found to be a risk factor for multiple sites of head and neck cancer. The ALDH2 variant had a relative risk of 5.7 for multiple sites, and in combination with the allele of the ADH3-2 enzyme led to an increased relative risk of 14 in patients with multiple Lugol-negative areas. Multiple Lugol-negative areas in the esophagus thus indicate a high risk for multiple cancers both in the esophagus and the head and neck region.

Accumulation of acetaldehyde, a toxic and carcinogenic agent, is a consequence of gene polymorphism and is mediated by variants of the ADH3 and ALDH-2 enzymes responsible for the metabolism of ethanol. Multiple occurrences of neoplastic lesions in the airways and upper gastrointestinal tract have been explained by the concept of “field cancerization”, usually associated with repeated exposure to carcinogens such as alcohol and tobacco. Ethanol is metabolized by ADH into acetaldehyde, and acetaldehyde, a highly toxic intermediate product of ethanol, is metabolized into acetic acid by ALDH. In Asia, particularly in Japan, a large proportion of the population (50 % in Japan) have ineffective forms of the enzymes involved in the alcohol metabolism, with combinations of the slow ADH3 and the ineffective ALDH-2 variant. Persistent heavy drinking despite unpleasant reactions to acetaldehyde in individuals who have the ineffective enzyme is probably explained by the very gradual accumulation of acetaldehyde in the presence of the slow-acting ADH3-2 allele. These individuals should be strongly recommended to refrain from alcohol and to participate in screening programs to ensure early detection of cancer.

To identify such patients, it has been suggested that the flushing test can be used to assess both current and past flushing, detecting inactive ALDH2. The facial flushing questionnaire was tested in Japan in 233 men with esophageal squamous-cell carcinoma and 610 men without cancer [2]. When individuals with current or former flushing were regarded as having inactive ALDH2, the sensitivity and specificity of the test were 84.8 % and 82.3 %, respectively, for the cases and 90.1 % and 88.0 %, respectively, for the controls.

References

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