Association between aldehyde dehydrogenase gene polymorphisms and the phenomenon of field cancerization in patients with head and neck cancer.

M Muto

doi:10.1093/carcin/23.10.1759

Abstract

Patients with squamous-cell carcinoma in the head and neck (HNSCC) often develop second primary esophageal squamous-cell carcinomas (ESCC). In addition, widespread epithelial oncogenic alterations are also frequently observed in the esophagus and can be made visible as multiple Lugol-voiding lesions (multiple LVL) by Lugol chromoendoscopy. Multiple occurrences of neoplastic change in the upper aerodigestive tract have been explained by the concept of 'field cancerization', usually associated with repeated exposure to carcinogens such as alcohol and cigarette smoke. However, the etiology of second ESCC in HNSCC patients remains unclear and acetaldehyde, the first metabolite of ethanol, has been implicated as the ultimate carcinogen in alcohol-related carcinogenesis. We first investigated the relation between second ESCC and multiple LVL in 78 HNSCC patients. Multiple LVL and second ESCC were observed in 29 (37%) and 21 (27%) patients, respectively. All of the second ESCC were accompanied by multiple LVL. This may indicate that episodes of multiple LVL are precursors for second ESCC. We then examined the association of multiple LVL with the patients' characteristics, including genetic polymorphisms of the alcohol metabolizing enzymes, alcohol dehydrogenase type 3 (ADH3) and aldehyde dehydrogenase type 2 (ALDH2). We also investigated acetaldehyde concentrations in the breath of 52 of the 78 patients. All the patients with multiple LVL were both drinkers and smokers. Multivariable logistic analysis showed that the inactive ALDH2 allele (ALDH2-2) was the strongest contributing factor for the development of multiple LVL (odds ratio 17.6; 95% confidence intervals 4.7-65.3). After alcohol ingestion, acetaldehyde in the breath was elevated to a significantly higher level in all patients with the ALDH2-2 allele than in those without it. The high levels of breath acetaldehyde were significantly modified by the slow-metabolizing ADH3-2 allele. These results reveal strong evidence for a gene-environmental interaction between the ALDH2-2 allele and alcohol consumption, for the risk of developing multiple LVL, resulting in the development of second ESCC in patients with HNSCC. Ultimately, increased local acetaldehyde exposure thus appears to be a critical determinant of the phenomenon of 'field cancerization'.

Highlights

Patients with HNSCC, especially in the oral cavity, oropharynx and hypopharynx, often develop second primary esophageal squamous cell carcinoma (ESCC) [1,2,3,4,5]
The present data demonstrate a clear association between multiple multiple Lugol-voiding lesions (LVL) and second ESCC in patients with HNSCC. This finding suggests that episodes of multiple LVL are precursors of second ESCC in such patients
We found a strong association between the development of multiple LVL and the ALDH2-2 allele in patients with HNSCC

Summary

Introduction

Patients with HNSCC, especially in the oral cavity, oropharynx and hypopharynx, often develop second primary ESCC [1,2,3,4,5] In such patients, widespread epithelial oncogenic alterations, such as several grades of squamous epithelial dysplasia, frequently occur in the upper aerodigestive tract including the esophagus [6,7]. Widespread epithelial oncogenic alterations, such as several grades of squamous epithelial dysplasia, frequently occur in the upper aerodigestive tract including the esophagus [6,7] They are clinically detected as multiple Lugolvoiding lesions (multiple LVL) by Lugol chromoendoscopy [8], since Lugol-dye does not stain such lesions [9]. Identification of the etiology underlying the phenomenon of field cancerization might help to explain why some patients with HNSCC have a high likelihood of developing a second ESCC, and this will have a great impact on designing effective prevention, early diagnosis and therapeutic strategies

Methods

Results

Conclusion