Approximately 8% of the world population and 35–45% of East Asians are carriers of the hereditary disorder aldehyde dehydrogenase 2 (ALDH2) deficiency. ALDH2 plays a central role in the liver to metabolize ethanol. With the common E487K variant, there is a deficiency of ALDH2 function; when ethanol is consumed, there is a systemic accumulation of acetaldehyde, an intermediate product in ethanol metabolism. In ALDH2-deficient individuals, ethanol consumption acutely causes the “Alcohol Flushing Syndrome” with facial flushing, tachycardia, nausea, and headaches. With chronic alcohol consumption, ALDH2 deficiency is associated with a variety of disorders, including a remarkably high risk for aerodigestive tract cancers. Acetaldehyde is a known carcinogen. The epidemiologic data relating to the association of ALDH2 deficiency and cancer risk are striking: ALDH2 homozygotes who are moderate-to-heavy consumers of ethanol have a 7–12-fold increased risk for esophageal cancer, making ALDH2 deficiency the most common hereditary disorder associated with an increased cancer risk. In this review, we summarize the genetics and biochemistry of ALDH2, the epidemiology of cancer risk associated with ALDH2 deficiency, the metabolic consequences of ethanol consumption associated with ALDH2 deficiency, and gene therapy strategies to correct ALDH2 deficiency and its associated cancer risk. With the goal of reducing the risk of aerodigestive tract cancers, in the context that ALDH2 is a hereditary disorder and ALDH2 functions primarily in the liver, ALDH2 deficiency is an ideal target for the application of adeno-associated virus-mediated liver-directed gene therapy to prevent cancer.
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We thank N. Mohamed for editorial assistance.
These studies were supported, in part, by NIH R41AA027739 and R41AA028465.
RGC is a consultant and holds equity in LEXEO Therapeutics; LEXEO has an option with Weill Cornell Medical College to license the ALDH2 gene therapy program. RGC is also a co-inventor on a patent application related to this topic (US application number 16/321,023).
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Montel, R.A., Munoz-Zuluaga, C., Stiles, K.M. et al. Can gene therapy be used to prevent cancer? Gene therapy for aldehyde dehydrogenase 2 deficiency. Cancer Gene Ther 29, 889–896 (2022). https://doi.org/10.1038/s41417-021-00399-1