Perhaps based on this prospective study and many other articles, the US Surgeon General identified heavy alcohol consumption as a potential cause of many cancers. There are several biological mechanisms. See Four ways alcohol can cause cancer.

All of them remind me of cancer biology courses I took a decade ago. I agree alcohol can cause cancer in some ways, but proving the causality and measuring causal effect sizes will probably be another research question. Showing tobacco causes cancer took nearly a half-century from the earliest wakeup calls until the US Surgeon General finally acknowledged the fact, and perhaps longer until the tobacco companies took meaningful action.

I am wondering if there are any (genetic) instrumental variables to establish some sense of causality. Well... In fact, there are some:

• Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people

  • No wonder several alcohol intake GWAS variants are located in biochemically-relevant genes, including ALDH1B and ALDH2; they are also "colocalized" in interaction analysis with cancer GWAS studies.

• Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

  • "Another possibility is that light-to-moderate drinking has a protective effect on risk of colorectal cancer, even though heavier consumption is detrimental." This clearly sets their questions and why they designed the study to show in which direction effects could go.

  • Also, G x E interaction analysis with stratification--non-drinking, light-drinking, and heavy-drinking. We see some significant hits (why?), and they end up with somewhat bizarre conclusion: "Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers." What about the other variants?

  • What if drinking behaviour is a mediator variable (genetic variant to drinking to cancer)? The stratification step could create artificial associations between genetic variants and cancer phenotypes.

• The causal effects of genetically predicted alcohol consumption on endometrial cancer risk from a Mendelian randomization study

  • Summary-based MR analysis.

  • Also, a bit weird conclusion: "This MR study suggests that genetically predicted alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1."

  • What if people abstained from drinking because of health concerns, such as a family history of endometrial cancer? IV assumptions would be easily invalid. EC GWAS is also sampled from the same UK Biobank cohorts, which could put the study design in a precarious position.

Okay, I may want to believe that alcohol is a cause of cancer. But I don't think we have a definitive answer to the underlying causal questions. Studies often disagree with each other. It's like opening up another decade of debate among researchers, policymakers, and the general public. However, I don't think we are missing a chance to potential protective effects of alcohol by not cutting down on drinking. A more constructive way forward will be looping in molecular mechanisms in causal inference exercises. We identified the mechanisms in laboratory settings. How does it work at a population level? Are there alcohol-interaction molecular QTL studies? Shouldn't we consider gene-gene interactions and compensatory mechanisms? Lots of "could've done" items.