Critique 001: Genes, alcohol, breast cancer

International Scientific Forum on Alcohol Research

Critique 001: 24 April 2010

Subject:  Genes, alcohol, breast cancer

Genetic effects on alcohol metabolism modify the relation of alcohol to breast cancer ____________________________________________________________________________________

Article:   Larsen SB, Vogel U, Christensen J, Hansen RD, Wallin H, Overvad K, Tjønneland A, Tolstrup I.    Interaction between ADH1C Arg²⁷²Gln and alcohol intake in relation to breast cancer risk suggests that ethanol is the causal factor in alcohol related breast cancer.  Cancer Letters, 2010, in press.

Authors’ Abstract

Alcohol is a risk factor for breast cancer.  We wanted to determine if ADH polymorphisms which modify the rate of ethanol oxidation to acetaldehyde were associated with breast cancer risk.  We matched 809 postmenopausal breast cancer cases with 809 controls, nested within the prospective Diet, Cancer and Health study. Among variant allele carriers of ADH1C Arg²⁷²Gln, alcohol intake increased the risk of breast cancer with 14% (95% CI: 1:04 – 1.24) per 10 g alcohol/day, but not among homozygous wild carriers (p for interaction =0.06).  Thus, slow oxidation of ethanol seemed to be associated with breast cancer risk

Comments of Forum:  This new paper (in press) compares different genotypes of the ADH (alcohol dehydrogenase) gene among 809 women with breast cancer and 809 controls to determine if certain polymorphisms relate to breast cancer risk associated with alcohol consumption.  Among drinkers, the investigators found an increase in risk of breast cancer with alcohol intake for subjects with ADH1C alleles that relate to slow clearance of alcohol from the blood, but not among women with other alleles.  This would suggest that women who maintain higher blood levels of alcohol for a longer time after drinking (due to slow metabolism of alcohol) may have higher breast cancer risk, whereas those who clear alcohol from the blood stream more quickly may not be at increased risk of breast cancer from alcohol intake.

Unfortunately, these results are different from some other papers on the topic.  For example, Frendenheim et al¹ reported that subjects with AHD3 genotypes that lead to fast clearance of alcohol had higher risk of breast cancer associated with alcohol consumption; a similar finding was reported by Terry et al² .  On the other hand, Strümer et al³ found that drinking women with ADH 2 phenotypes associated with slow clearance of alcohol had higher risk of breast cancer.  A recent study from Japan by Kawase T, et al⁴ found no statistically significant association between genetic factors leading to slow or fast metabolism of alcohol and risk of breast cancer.  It may also be relevant that Tolstrup et al⁵ evaluated ADH genotypes as potential modifiers of alcohol’s effects on cardiovascular risk; while finding strong effects of alcohol on cardiovascular disease and risk factors, they found that the associations were not modified by ADH1B and ADH1C genotypes.

Besides the inconsistency with previous epidemiological evidence, some important information is missing from the present paper:  (a) the actual values of ethanol and acetaldehyde; (b) the relevance of alternative pathways for ethanol metabolism (producing oxidants but not reductants as the dehydrogenase pathway); (c) the actual total mortality (or morbidity); (d) information about qualitative – and quantitative –  food intake.  It is clear that genetic phenotypes could increase or decrease an individual’s risk of breast cancer from alcohol consumption, as these are functional gene variants.  However, more research in different populations is necessary, as the effect of such low-penetrance gene variations can be masked by other more important/prevalent polymorphisms.

Overall, we believe that the scientific data are inconclusive as to the effects of genetic factors affecting the rate of alcohol metabolism on the risk of breast cancer associated with alcohol.  While studies such as this one may help scientists understand the mechanisms by which alcohol may relate to breast cancer risk, a clear message to the public on this topic is not yet possible.  Making conclusions on causation from a single epidemiological result, although deserving the merit of bringing to light issues worth to be studied in depth, could be relatively risky when used to support health claims. The consensus between different studies must be robust and a biologically sound mechanism, at least tentative, must be proposed.  Further, these polymorphisms affecting ADH relate not only to breast cancer, but to more common conditions such as coronary heart disease, and it would be important to know the net effects of these genes on morbidity and mortality.

References to earlier reports

1.             Freudenheim JL, et al.  Alcohol dehydrogenase 3 genotype modification of the association of alcohol consumption with breast cancer risk.  Cancer Causes and Control 1999;10:369-377.

2.             Terry MB, et al.  ADH3 genotype, alcohol intake and breast cancer.  Carcinogenesis 2006;27:840-847.

3.             Stürmer T, et al, Interaction between alcohol dehydrogenase II gene, alcohol consumption, and the risk of breast cancer.  Br J Cancer 2002;87:519-523.

4.             Kawase T, et al.  Interaction of the effects of alcohol drinking and polymorphisms in alcohol -metabolizing enzymes on the risk of female breast cancer in Japan.  J Epidemiol 2009;19:244-250.

5.             Tolstrup JS, et al.  Alcohol intake, myocardial infarction, biochemical risk factors, and alcohol dehydrogenase genotypes.  Circ Cardiovasc Genet 2009;2:507-514.

Lay Summary:  This study from Germany is a case-control comparison of the association between alcohol and breast cancer according to genetic variations affecting levels of alcohol dehydrogenase, an enzyme that clears alcohol from the blood stream.  The authors conclude that genetic factors associated with the slow clearance of alcohol are associated with increased risk of breast cancer for drinkers; an increase in cancer risk was not seen for drinkers with genetic factors leading to fast clearance of alcohol.  Such a finding would suggest that alcohol itself is the cause of an increase in breast cancer risk among drinkers.

Unfortunately, some previous studies have shown the opposite, that an increase in breast cancer risk occurs only among women who have genes associated with fast, rather than slow, alcohol metabolism.  Breast cancer’s relation to drinking is not resolved, remaining murky and conflicted, and perhaps overemphasized. This facet of that murkiness is itself also conflicted.  As of now, it is unclear the degree to which genes affecting alcohol dehydrogenase modify the association between alcohol and breast cancer risk.

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Contributions to this critique by the International Scientific Forum on Alcohol Research were made by

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Maritha Kotze, PhD, University of Stellenbosch, Stellenbosch, South Aftica

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy;

R. Curtis Ellison, MD, Epidemiology, Boston University School of Medicine, Boston, MA, USA