Association of aldehyde dehydrogenase 2 gene polymorphism with multiple oesophageal dysplasia in head and neck cancer patients

Abstract

Background: Multiple occurrences of oesophageal dysplasia are frequently observed in head and neck cancer patients, and closely associated with alcohol consumption. Acetaldehyde, the first metabolite of ethanol, is thought to play an important role in the carcinogenesis of the upper aerodigestive tract.

Aim: To investigate if genetic polymorphism in alcohol metabolising enzymes (ADH3, alcohol dehydrogenase 3; ALDH2, aldehyde dehydrogenase 2) is associated with oesophageal multiple dysplasia in head and neck cancer patients.

Methods: Thirty one consecutive patients with head and neck cancer were included in the study. Multiple oesophageal dysplasia was detected endoscopically as multiple Lugol voiding lesions (multiple LVL) using the Lugol dye staining method. The ADH3 and ALDH2 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism.

Results: Among the 31 patients with head and neck cancer, 17 had multiple LVL. Multiple LVL were closely associated with a second primary oesophageal carcinoma in head and neck cancer patients (odds ratio 60.7, 95% CI 5.6-659). Furthermore, the mutant ALDH2 allele was significantly more prevalent in patients with multiple LVL (65% v 29%; p<0.05) whereas no difference was observed in ADH3 polymorphism.

Conclusions: The mutant ALDH2 allele appears to be a risk indicator for multiple LVL in head and neck cancer patients. Accumulation of acetaldehyde due to low ALDH2 activity may play a critical role in cancerous changes throughout the mucosa in the upper aerodigestive tract.

Figure 1

Endoscopic images of the oesophagus in a patient with head and neck cancer (A-D). Conventional endoscopic images (A, C) showed no abnormalities. After application of Lugol dye solution, multiple well defined, irregular shaped, yellowish white multiple Lugol voiding lesions (LVL) were seen scattered throughout the oesophageal mucosa (B, D).

Figure 2

Histological examination of multiple Lugol voiding lesions (LVL). The biopsy specimen taken from some of the multiple LVL showed severe dysplasia (A). The endoscopically resected specimen of the largest LVL in fig 1B revealed squamous cell carcinoma in situ (B).

Figure 3

Representative electrophoretic patterns of the ADH3 genotype analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) from three patients with the ADH3^1-1, ADH3^1-2, and ADH3^2-2 genotypes. The ADH3¹ allele yielded 67 bp, 63 bp, and 15 bp fragments, and the ADH3² allele appeared as a 130 bp and a 15 bp fragment. The undigested PCR product for ADH3 (ADH3 non-cut) is shown for comparison (lane 1). A 100 bp marker ladder served as a reference for DNA fragment size (M, lane 5).

Figure 4

Representative electrophoretic pattern of the ALDH2 genotype analysed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) from three patients with ALDH2-1/2-1, ALDH2-1/2-2, and ALDH2-2/2-2 genotypes. The ALDH2-1 allele yielded a 125 bp fragment and the ALDH2-2 allele appeared as a 134 bp fragment. The undigested PCR product for ALDH2 (ALDH2 non-cut) is shown for comparison (lane 1). A 100 bp marker ladder served as a reference for DNA fragment size (M, lane 5).