Alcohol, an ALDH2 Gene Mutation, and Esophageal Cancer

choi

(1) C Claiborne Ray, Red in the Face. New York Times, May 6, 2014.
www.nytimes.com/2014/05/06/science/red-in-the-face.html
(a mutation in aldehyde dehydrogenase 2 raises the risk of esophageal cancer by alcohol consumption)

My comment: If a person have two copies of mutated gene and overcomes the side effects of aldehyde accumulation in blood (eg, through strong will, as this does happen), that person’s risk is even higher than another person with just ONE copy of mutated gene, everything else being equal (such as alcoholic consumption).

choi

(2) Brooks PJ, The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. PLoS Med, 6: e1000050 (2009; review).
www.ncbi.nlm.nih.gov/pmc/articles/PMC2659709/?tool=pubmed

Quote:

"Approximately 36% of East Asians (Japanese, Chinese, and Koreans) show a characteristic physiological response to drinking alcohol that includes facial flushing * * * nausea, and tachycardia [meaning quick heartbeats] . This so-called alcohol flushing response * * * is predominantly due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2).

"Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) into acetaldehyde, a mutagen and animal carcinogen that causes DNA damage and has other cancer-promoting effects. Acetaldehyde is subsequently metabolized to acetate, mainly by the enzyme ALDH2  In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys). The Glu allele * * * encodes a protein with normal catalytic activity, whereas the Lys allele * * * encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold.

"Following the first study [in 1996], which was conducted in the Japanese population, case control studies in Japan and Taiwan have consistently demonstrated a strong link between the risk of esophageal squamous cell carcinoma (Figure 3) and alcohol consumption in low-activity ALDH2 heterozygotes

"It is important to note that ALDH2 deficiency does not influence esophageal cancer risk in non-drinkers.

"increasing evidence points to the metabolism of ethanol by microorganisms in the oral cavity as an important source of acetaldehyde in saliva and, by extension, in the esophagus.

"smoking further increases the esophageal cancer risk in a synergistic manner with alcohol

Note:
(a) Aldehyde dehydrogenase (ALDH) is actually a gene family, with the same function.
HUGO Gene Nomenclature Committee (HGNC), HUman Genome Organisation (HUGO; a private international organization established in 1989), undated.
www.genenames.org/genefamily/aldh.php

In the family, ALDH2, somehow (because I do not have time to find out, but it must have been elucidated) is the one isozyme (in plain English: the enzyme form among the family members) to do the job in a meaningful way that counts. ALDH2 is found in mitochondria but the gene encoding it (ALDH2) is in (human) chromosome 12. Westerners almost do not have the described mutation (Glu to Lys).
(b) It has not been worked out what form of aldehyde causes esophageal cancer--the one in the blood or the other found in the saliva (see quotation 5).
(c) Figure 5 of the review indicates that alcohol consumption increases risk of esophageal cancer, and that the more one drink, the higher the risk (of esophageal cancer)--whether the drinkers carry two copies of normal ALDH2 ("never-flusher") or mutated one ("flusher"), the difference being flushers are MORE at risk for the same level of alcoholic consumption.

(d) The review stated, "Consistent with the results of case control studies, prospective studies in cancer-free alcoholics have also shown that the relative hazard for future upper aerodigestive tract (UADT) cancers in low-activity ALDH2 heterozygotes is approximately 12 times higher than in individuals with active ALDH2 [15]. (The UADT includes the oral cavity, pharynx, larynx, and esophagus.)"

definition:
aerodigestive tract: "The combined organs and tissues of the respiratory tract and the upper part of the digestive tract (including the lips, mouth, tongue, nose, throat, vocal cords, and part of the esophagus and windpipe)"
NCI Dictionary of Cancer Terms
www.cancer.gov/dictionary?cdrid=44811