Source: Singularity Network
Have you ever had a similar myth: some friends around you, crazy stay up late liver papers, fried chicken milk tea happy water non-stop, only sleep 5 hours a day is still alive, and yourself, but where you sleep for an hour late, the next day will be brain blank, heart rate is too fast, eyes are unfocused, non-stop hair loss ...
Although it must be admitted that it is true that bad living habits are not good, how can someone be so "carried"? For example, drinking alcohol is not good for the liver, which is a common sense, but in fact, a considerable number of long-term alcoholics do not develop liver cancer.
In a recent article published in The Lancet Oncology, scientists from France and Belgium conducted a genome-wide association study (GWAS) that explored the role of pathogenic genes associated with alcohol-related hepatocellular carcinoma (HCC) in the population genetic process. They found a pair of genes, WNT3A-WNT9A, which may be associated with alcohol consumption-related HCC, which may play an early role in the Wnt-β-catenin pathway associated with the development of liver cancer. This is also the first GWAS in this class of patients [1].
Alcohol-related liver disease accounts for nearly one-third of the world's HCC patients [2]. Some clinical studies have found that risk factors associated with alcohol consumption that may lead to HCC include advanced age, males, and liver fibrosis, but some people who drink alcohol for a long time and occupy the above risk factors do not progress to HCC [2-4], indicating that in addition to environmental factors, individual genetic differences also play a decisive role.
Past GWAS studies have identified two common monoceric acid base mutations associated with an increased risk of HCC: rs738409 (C>G) in PNPLA3 and rs58542926 (C>T) in TMSF2 [5,6], and rs72613567 (T>TA) in HSD17B13 associated with reduced HCC risk.[7]
This study conducted a GWAS study of these common mononucleic acid base mutations that have been identified to help us better understand the effects of these genes in alcohol-related HCC and liver carcinogenesis.
The study was conducted in European patients with alcohol-related liver disease who were not related and were divided into three phases: discovery cohort, validation cohort, and meta-analysis.
In the discovery cohort, the researchers analyzed samples from 775 HCC patients (case group) versus 1332 non-HCC liver disease patients (non-case group) and showed that rs8107974 in the SUGP1 gene was in a highly interlocking imbalance with rs5852926 in TM6SF2, meaning that the base pairs 7974 and 2926 were more likely to co-inherit. Similarly, rs2294915 and rs738409 in PNPLA3, rs708113 in WNT3A-WNT9A and two other mononucleic acid base pairs in the same region are also in a highly interlocking imbalance state.
The gene HSD17B13, which is associated with a reduced risk of HCC, was also validated in the discovery cohort, but did not achieve significant differences in the GWAS level. Notably, in the cohort of findings, the researchers identified a third gene associated with an increased risk of HCC: WNT3A-WNT9A. They were also confirmed in the validation cohort that these three genes were indeed associated with an increased risk of HCC.
The researchers also looked at the relationship between the number of people carrying genetic mutations and the risk of alcohol-related HCC in a meta-analysis. According to the results of the analysis, there is an additive effect between the number of mutations carried and the incidence of alcohol-related HCC, that is, the more mutations carried, the greater the risk of alcohol-related HCC. Even after adjusting for the confounding factors of age, sex and stage of liver fibrosis, the results were still the same.
Different numbers of risk allele carriers are at risk of HCC
Overall, the analysis of the above three stages first confirmed that four gene mutations (three increases and one decrease) were associated with alcohol-related HCC risk, but the effects of mutations with reduced risk were not significant enough. In addition, the more mutations carried, the higher the risk of developing HCC, regardless of age, sex, and other factors.
In addition, in order to compare with other types of chronic liver disease (chronic hepatitis C, chronic hepatitis B, non-alcoholic fatty liver), the researchers also did AGWAS studies in patients with the above three types of chronic liver disease. They found that rs708113 in the WNT3A-WNT9A gene was not associated with the risk of developing HCC from these three chronic liver diseases, while the other three mutations were significantly associated with the risk of developing HCC from non-alcoholic fatty liver disease.
The researchers extracted non-tumor tissue from alcohol-associated HCC patients and found that mutations in the WNT3A-WNT9A rs708113[T] base pair were associated with high expression of inflammatory factors and natural killer cells.
At the same time, they also studied the difference in the expression level of this gene in patients with alcohol-associated HCC and patients with non-alcohol-related HCC. Before doing so, let's briefly understand a genetic mutation common in patients with alcohol-associated HCC, the CTNNB1 gene mutation, which is associated with activation of the Wnt-β-catenin pathway and low immune infiltration in the tumor environment, both of which are associated with the occurrence of HCC [8,9].
The researchers found that there were more mutations in the CTNNB1 gene in patients with alcohol-related HCC than in patients with non-alcohol-related HCC, but in patients with alcohol-related HCC, patients with WNT3A-WNT9A rs708113 mutations had a decrease in mutations in the CTNNB1 gene. The "seesaw" balance of these two gene mutations was associated with the amount of alcohol consumed, and the researchers found their correlation only in HCC patients who drank alcohol.
So far, this study has demonstrated the correlation between the common genetic mutations found and alcohol-related HCC at the gene level, and completed the discovery and verification of WNT3A-WNT9A rs708113. Because WNT3A and WNT9A encode ligands of the Wnt-β-catenin pathway [10] and play an important role in the development, metabolism, and liver carcinization of liver disease, mutations in this pathway may seriously affect signal transduction of regulatory genes.
Alcohol-related HCC generally has a poor prognosis, and these findings affirm the important role of the WNT3A-WNT9A locus in the pathogenesis of alcohol-related HCC and may be potential targets in the future treatment of alcohol-related HCC. However, whether the rs708113 mutation has an effect on the expression of WNT3A-WNT9A in tumor tissue, or whether it directly affects the tumor microenvironment, still needs to be explored.
bibliography:
1. Eric Trépo, et al. Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study, The Lancet Oncology, 2021,
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