Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

doi:10.1053/j.gastro.2009.07.070

Gastroenterology

Volume 137, Issue 5, November 2009, Pages 1768-1775

https://doi.org/10.1053/j.gastro.2009.07.070 Get rights and content

Background & Aims

Esophageal squamous cell carcinoma (ESCC) is prevalent among Asian populations, with marked regional variations in incidence and mortality. Patients with ESCC have a very poor prognosis, but detection of ESCC at earlier stages could improve clinical outcome. Therefore, identification of epidemiologic factors that influence the development of ESCC would facilitate prevention and/or early detection of the disease.

Methods

We performed a 2-step genome-wide association study with subsequent replication analysis using a total of 1070 Japanese ESCC cases and 2836 controls. We also used logistic regression analysis to estimate the effect of gene-gene and gene-environmental interactions.

Results

We identified the significant associations of ESCC with 4q21-23 and 12q24 regions, which include nonsynonymous single nucleotide polymorphisms (SNP) in ADH1B (rs1229984, P = 6.76 × 10⁻³⁵) and ALDH2 (rs671, P = 3.68 × 10⁻⁶⁸) that were previously shown to be associated with ESCC susceptibility. Multiple logistic regression analysis revealed SNP rs671, rs1229984, alcohol drinking, and smoking as the independent risk factors for ESCC (odds ratios of 1.66, 1.85, 1.92, and 1.79, respectively). Moreover, individuals who had both genetic and lifestyle-related risk factors had a nearly 190 times higher risk of ESCC than those who had neither of these.

Conclusions

We found 2 known functional variants involved in the metabolism of alcohol and tobacco by-products as the most significant risk factors for the development of ESCC in a Japanese population. The individuals carrying both risk genotypes have a higher baseline risk of ESCC that is substantially increased by 2 lifestyle risk factors.

Section snippets

Study Population

In this study, we conducted a 2-step genome-wide association study consisting of a screening phase and a subsequent replication analysis using a total of 1070 cases and 2836 control subjects. Characteristics of each cohort group are shown in Supplementary Table 1. All patients with ESCC as well as controls in the second stage and replication analysis were obtained from BioBank Japan,¹⁰ “the Leading Project for Personalized Medicine” in the Ministry of Education, Culture, Sports, Science and

Results

To identify common variants that influence ESCC risk, we genotyped 561,466 SNPs for 188 Japanese patients with ESCC and 938 control samples using Illumina HumanHap550v3 Genotyping BeadChip (Supplementary Figure 1A). Then, we further analyzed the top 12,000 SNPs in the first stage using an independent cohort consisting of 517 cases and 548 controls (Supplementary Figure 1B). Examination of the quantile-quantile plots of the first and second analyses revealed an enrichment of significant P

Discussion

Alcohol consumption was shown to increase various cancer risks,²³ but pure ethanol was shown not to act as a carcinogen in animal studies.²⁴ Acetaldehyde, a primary metabolite of ethanol, is considered to be a plausible candidate to have carcinogenic effects; in fact, acetaldehyde inhalation was shown to induce various types of tumor, particularly adenocarcinoma and squamous cell carcinoma of the nasal mucosa, in animal models.25, 26 In the present study, we conducted the first genome-wide

Acknowledgments

The authors thank the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting the study and the technical staff of the laboratory for genotyping at the Institute of Physical and Chemical Research (RIKEN) for technical assistance.

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: Conflicts of interest The authors disclose no conflicts.

: Funding This study was conducted as a part of Biobank Japan, funded by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

View full text

Basic—Alimentary TractFunctional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Population

Results

Discussion

Acknowledgments

Ann Oncol

Prog Nucleic Acid Res Mol Biol

Lancet

Ann Oncol

Toxicology

Eur J Cancer Clin Oncol

Alcohol

Global cancer statistics, 2002

CA Cancer J Clin

Gene-expression profile changes correlated with tumor progression and lymph node metastasis in esophageal cancer

Clin Cancer Res

Cancer statistics, 2008

CA Cancer J Clin

Time trends in cancer mortality in China: 1987–1999

Int J Cancer

Role of macronutrients, vitamins and minerals in the aetiology of squamous-cell carcinoma of the oesophagus

Int J Cancer

Genome-wide association study in esophageal cancer using GeneChip mapping 10K array

Cancer Res

Genetic polymorphisms of cytochrome P4501A1 and oesophageal squamous-cell carcinoma in Taiwan

Br J Cancer

Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics

Carcinogenesis

The BioBank Japan Project

Clin Adv Hematol Oncol

Two-stage designs for gene-disease association studies

Biometrics

Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies

Nat Genet

A high-throughput SNP typing system for genome-wide association studies

J Hum Genet

Principal components analysis corrects for stratification in genome-wide association studies

Nat Genet

Basic—Alimentary Tract
Functional Variants in ADH1B and ALDH2 Coupled With Alcohol and Smoking Synergistically Enhance Esophageal Cancer Risk