S629 It Is Good to Know if You Glow: A Scoping Review of ALDH2 Mutations and Guidelines for Esophageal Cancer

Introduction: People with ALDH2 deficiency, known as Alcohol Flushing Syndrome or “Asian Glow” are unable to metabolize alcohol properly, and thus are exposed to higher acetaldehyde levels. ALDH2 is a mitochondrial enzyme found in the liver and mucosa of the upper intestinal tract and is responsible for the oxidation of acetaldehyde. Globally, this deficiency affects 540 million people—8% of the world population. People with ALDH2 deficiency are 2 to 12 times more likely to develop esophageal cancer compared to people with normal ALDH2. Methods: We searched Electronic Databases: PubMed, Embase. Using keywords and MeSH terms including "esophageal cancer", "ALDH2 mutations", "screening", "screening guidelines", "genetic mutations", "esophageal neoplasms", etc. We included guidelines for esophageal cancer screening. We excluded studies not addressing esophageal cancer screening and studies not published in English. Two reviewers independently screened titles and abstracts of the identified studies. Results: Guidelines in Europe did discuss alcohol as a risk factor; with differences in diet/lifestyle leading to high rates of esophageal cancer but did not have screening recommendations. The Chinese national screening guideline for esophageal cancer recommends endoscopy screening for high-risk groups including age of >40, live in endemic regions, family history, and, pickled food, and poor dental hygiene.In Japan, guidelines focused on risk factors including drinking/smoking. Korean alcohol use guideline recommends decreased intake of alcohol by half in those with flushing rection.The NCCN guidelines (USA) and Canada focuses on screening those with genetic mutations such RHBDF2, Familial Barrett esophagus (FBE) Bloom syndrome, Fanconi anemia, those with BE, history of GERD, age >40, and are White. Other studies ranged in quality from meta-analysis of esophageal cancer risk to prospective studies proposing screening through MCV and acetaldehyde breath testing. Conclusion: ALDH2 has been studied mostly in East Asian countries. Despite meta-analysis and case-control studies showing the increased risk of esophageal cancer with ALDH2 mutation, no guidelines mention ALDH2 as a risk factor of esophageal cancer. Guidelines mostly emphasized alcohol usage as a significant modifiable risk factor. Recent studies highlight potential use of MCV levels and a novel acetaldehyde breath test to further identify high-risk patients for esophageal cancer that may benefit from early screening (see Figure 1, Table 1).Figure 1.: Flow chart of the studies identification and selection process. Table 1. - Reviewing selected guidelines that discussed screening and non-review studies examining ALDH2 Authors, Year Year Country Study Design Results NCCN 2024 USA Guidelines EGD screening is recommended in RHBDF2 mutation (Esophageal cancer, tylosis with non-epidermolysis palmoplantar keratosis (PPK), and Howel-Evans syndrome), Familial Barrett esophagus, Bloom syndrome and Fanconi anemia Groulx et al. 2020 Canada EGD screening is not recommendedRisk factors for adenocarcinoma: Precancerous conditions (e.g., Barrett esophagus, esophageal dysplasia), age ≥ 50 yr, Male sex, family history, White, abdominal obesity and smoking Kitagawa et al 2023 Japan Risk factor: Concomitant use of tobacco and alcoholIdentifies acetaldehyde formed after consumption of alcoholic beverages as Group 1 carcinogen National Health Commission of the People’s Republic of China 2022 China Recommends EGD screening in high-risk patients.Risk factors: Age ≥40 yrs., Endemic areas, family history, smoking, heavy intake of alcohol, squamous carcinoma of head and neck or respiratory tract, preferring very hot or pickled food, or with poor oral hygiene Ng et al. 2023 Hong Kong Meta Analysis Inactivated ALDH2 genetic polymorphism shows greater alcohol dose-response curve risk for esophageal cancer compared to the general population Zhang et al. 2023 China ADH1B rs1229984 was significantly associated with an increased the risk of esophageal SCC Lee et al. 2019 Korea In individuals with flushing reaction, heavy alcohol consumption ( > 4 drinks/wk) was associated with increased risk of high-risk colorectal adenoma Mao et al. 2016 China ADH1B gene Arg47His variant is associated with the decreased esophageal cancer risk. However, when combined with drinking, smoking or male, Arg/Arg genotype of ADH1B Arg47His variant is associated with increase esophageal cancer risk Nezu et al. 2022 Japan Cohort StudiesCohort Studies High MCV is associated with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2), which is encoded by ALDH2*1/2*2 and ESCCRecommends utilization of MCV as a biomarker for identifying high risk patient of ESCC Sasaki et al. 2021 Japan Proportion of individuals with inactive ALDH2 (higher acetaldehyde-to-ethanol ratio detected by novel breath test*) was significantly higher in the SCC groups compared to healthy controls Sasaki et al. 2023 Japan Recurrent SCC patients after submucosal dissection had higher acetaldehyde-to-ethanol ratio (associated with inactive ALDH2; detected by novel breath test*), compared to those without metachronous recurrence Tajiri et al. 2022 Japan Inactivation of both ADH1B and ALDH2 was associated with metachronous ESCC Yang et al 2021 Taiwan Hereditary variations in ALDH2, CISH, ERCC5, and ADH1B is associated with multiple primary cancer incidence in those with esophageal cancer. Yokoyama et al. 2020 Japan 25.4% of Japanese patients treated by endoscopic resection for ESCC were suspected to be alcohol dependent (AUDIT score≥ 15)High AUDIT score (AUDIT score≥ 15) markedly increases the risk of metachronous HNSCC. Yokoyama et al. 2019 Japan Slow-metabolizing ADH1B*1/*1 genotype, inactive heterozygous ALDH2*1/*2 genotype, a low BMI and high MCV associated with esophageal neoplasia (defined by DIULs ≥5 mm, and multiple DIULs) in alcohol-dependent women and men. Yu et al 2018 China Low-activity ALDH2 was associated with increased EC risk AMONG male heavy alcohol consumersThe EC risk associated with the synergistic interaction between inactive ALDH2 and alcohol consumption underscores the importance of screening for the ALDH2 deficiency. Sugimoto et al. 2023 Japan Case Control Studies ADH1B Arg allele contributes to esophageal cancer risk by slowing alcohol breakdown, in addition to its effect on behavioral medication of alcohol consumption Iwasaki et al. 2020 Japan Gene-environment interaction model (environmental factors AND ALDH2 genotype) is a better predictor for ECC development than environmental model (Age, smoking status, alcohol consumption) Choi et al. 2021 Korea ALDH2 rs671 polymorphisms are associated with esophageal cancer, which may be due to acetaldehyde accumulation

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