Excessive drinking: genetic variations that protect against liver cancer


Jessica Zucman-Rossi’s team has just published in The Lancet Oncology the results of the first genome-wide association study (GWAS) conducted on more than 4,000 patients to assess the impact of genetic background on the development of liver cancer in heavy alcohol consumers.

Hepatocellular carcinoma (HCC) is the most common liver cancer and the third leading cause of cancer death worldwide. Liver disease related to excessive alcohol consumption is the leading cause of hepatocellular carcinoma in France and in many Western countries. Although the risk of developing liver cancer increases with the severity of alcohol-induced liver damage, liver cancer will only develop in a minority of chronic heavy drinkers suggesting the involvement of genetic factors. Understanding why some patients develop liver cancer and not others is the question that was asked by the team of Professor Jessica Zucman-Rossi at the Cordeliers Research Center (University of Paris, Inserm, Sorbonne University), and her collaborators in the GENTHEP network (Genetics of Liver Tumors) in France and Belgium.

In order to better evaluate a genetic predisposition favoring the occurrence of liver cancer related to alcohol consumption, the first genome-wide association study (GWAS) was conducted in more than 4000 patients recruited in several university hospital centers in France and Belgium, specialized in the screening and treatment of liver cancer. This type of study consists of comparing the genomes of thousands of individuals with a common phenotype or disease, in this case patients with chronic heavy drinking who developed liver cancer compared to patients with chronic heavy drinking who did not develop liver cancer.  The researchers identified the WNT3A-WNT9A genes as associated with the risk of developing hepatocellular carcinoma in patients with excessive alcohol consumption. These findings, published in The Lancet Oncology on December 10, 2021, provide insight into the mechanisms of interaction between lifetime alcohol exposure and genetic diversity in individuals leading to the development of liver cancer

Jessica Zucman-Rossi’s team has shown that certain genetic variations appear to be protective in the context of excessive and chronic alcohol consumption. Thus, patients carrying particular genetic variations in the WNT3A-WNT9A genes have a lower risk of developing HCC related to chronic alcohol consumption (more than 4 drinks per day). The researchers also confirmed that genetic variations in the PNPLA3, TM6SF2 and HSD17B13 genes modulated the risk of alcohol-related HCC. The simultaneous presence of risk variants in these 4 genes increased the risk of alcohol-related HCC. 

The team’s previous work showed that nearly half of alcohol-related HCCs had mutations in the CTNNB1 gene within the tumor tissue and activation of the Wnt-β-catenin signaling pathway, accompanied by a decrease in the presence of immune cells. The present study shows that the tumors of patients who developed alcohol-related HCC and carry the protective variation of the WNT3A-WNT9A genes are different. In these patients, the non-tumor region of the liver shows increased expression of inflammation-related genes. These results suggest that protective variants in the WNT3A-WNT9A genes would promote an inflammatory environment that itself would prevent activation of the Wnt-β-catenin signaling pathway and thus may help prevent alcohol-related liver carcinogenesis.

The harmful role of excessive alcohol consumption on the liver is well known. These results provide a better understanding of the mechanisms related to the development of alcohol-induced HCC and open new avenues of research to identify new therapeutic targets to fight liver cancer.

In any case, it is important to remember that limiting alcohol consumption has a very important impact and allows the effective prevention of liver cancer development. 

This work was financially supported by the Ligue Nationale contre le Cancer (Labellisée team), Bpifrance, INSERM (cancer plan), the Association Française pour l’Étude du foie, the Coup d’Elan de la Fondation Bettencourt-Schueller, the FRM Rosen prize, the Ligue Contre le Cancer Comité de Paris (René et André Duquesne prize), the Fondation Mérieux and the Université Libre de Bruxelles in Belgium.