Reply to: "Genetic factors in the clinical predictive model for hepatocellular carcinoma: Evidence from genetic association analyses"

Genetic factors in the clinical predictive model for hepatocellular carcinoma: Evidence from genetic association analysesJournal of HepatologyVol. 79Issue 1PreviewWe read with great interest the study by Pierre Nahon et al. where the traditional clinical model was improved to better predict the probability of hepatocellular carcinoma (HCC) development in patients with cirrhosis, by incorporating information on seven single nucleotide polymorphisms (SNPs), including rs738409 (PNPLA3), rs58542926 (TM6SF2), rs187429064 (TM6SF2), rs641738 (MBOAT7), rs72613567 (HSD17B13), rs429358 (APOE) and rs708113 (WNT3A-WNT9A).1 This study is thought-provoking and should have great potential application in clinical practice. Full-Text PDF Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosisJournal of HepatologyVol. 78Issue 3PreviewIdentifying individuals at higher risk of developing hepatocellular carcinoma (HCC) is pivotal to improve the performance of surveillance strategies. Herein, we aimed to evaluate the ability of single nucleotide polymorphisms (SNPs) to refine HCC risk stratification. Full-Text PDF We read with great interest the comment of Chen et al.[1]Chen L. Fan Z. Zhao Y. Yang H. Lv G. Genetic factors in the clinical predictive model for hepatocellular carcinoma: evidence from genetic association analyses.J Hepatol. 2023 Jan 3; (S0168-8278(22)03476-6. https://dx.doi.org/10.1016/j.jhep.2022.12.024)Abstract Full Text Full Text PDF Scopus (4) Google Scholar to our recent contribution to the Journal of Hepatology.[2]Nahon P. Bamba-Funck J. Layese R. Trepo E. Zucman-Rossi J. Cagnot C. et al.Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis.J Hepatol. 2022 Nov 22; (S0168-8278(22)03294-9. https://dx.doi.org/10.1016/j.jhep.2022.11.003)Abstract Full Text Full Text PDF Scopus (9) Google Scholar In their letter, the authors highlight that genetic variants associated with hepatocellular carcinoma (HCC) differ as a function of European or East Asian ancestry. Their opinion is supported by the analysis of previously published data from genome-wide association studies (GWASs) conducted in Asian[3]Ishigaki K. Akiyama M. Kanai M. Takahashi A. Kawakami E. Sugishita H. et al.Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.Nat Genet. 2020; 52: 669-679Crossref PubMed Scopus (189) Google Scholar and European[4]Trepo E. Caruso S. Yang J. Imbeaud S. Couchy G. Bayard Q. et al.Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.Lancet Oncol. 2022; 23: 161-171Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar populations (the latter being performed by our consortium in France and Belgium); they found that only PNPLA3 rs738409 was associated with HCC in both. While we fully agree that genetic variants pinpointed by those GWASs are influenced by allele frequencies and thus differ across ancestries, we also believe that the nature of the underlying chronic liver disease (CLD) causing HCC is a pivotal point to take into account. The Asian GWAS included more than 200,000 Japanese individuals and gathered 42 diseases, including 13 cancers. Patients with HCC had various underlying CLDs, but their distribution is not detailed in the original publication.[3]Ishigaki K. Akiyama M. Kanai M. Takahashi A. Kawakami E. Sugishita H. et al.Large-scale genome-wide association study in a Japanese population identifies novel susceptibility loci across different diseases.Nat Genet. 2020; 52: 669-679Crossref PubMed Scopus (189) Google Scholar It is, however, most likely that patients with HCV- or HBV-related HCC were included in the analysis, given the prevalence of viral hepatitis in Asia and that these patients had active viral replication at the time of HCC diagnosis. Conversely, our GWAS was dedicated to alcohol-related HCC, and we further explored top GWAS hits in cases and controls with HCV, HBV, and non-alcoholic fatty liver disease (NAFLD). It is well known that HCC development in patients with active viral replication is strongly impacted by a direct oncogenic role of the virus; this observation might partly explain the debated association of risk loci influencing liver fat content (e.g., TM6SF2) in HCV-related HCC, while more recent longitudinal studies similar to ours have suggested that genetic variants associated with steatosis may promote HCC development following viral eradication.[5]Degasperi E. Galmozzi E. Pelusi S. D'Ambrosio R. Soffredini R. Borghi M. et al.Hepatic fat-genetic risk score predicts hepatocellular carcinoma in patients with cirrhotic HCV treated with DAAs.Hepatology. 2020; 72: 1912-1923Crossref PubMed Scopus (39) Google Scholar This observation is in line with the results of our GWAS,[4]Trepo E. Caruso S. Yang J. Imbeaud S. Couchy G. Bayard Q. et al.Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study.Lancet Oncol. 2022; 23: 161-171Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar which also included patients with viral-induced HCC as comparators: in this subgroup, variants in TM6SF2, WNT3A-WNT9A reaching GWAS significance (p <5x10-8) in patients with alcohol-related liver disease (ALD) were not significantly (p >0.05) associated with HCC. These findings align with those of Chen et al. in the East Asian GWAS. In contrast, the prospective French cohorts included in the scoring system article[2]Nahon P. Bamba-Funck J. Layese R. Trepo E. Zucman-Rossi J. Cagnot C. et al.Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis.J Hepatol. 2022 Nov 22; (S0168-8278(22)03294-9. https://dx.doi.org/10.1016/j.jhep.2022.11.003)Abstract Full Text Full Text PDF Scopus (9) Google Scholar included patients with HCV-related cirrhosis and sustained virological response (SVR), in whom some variants modulating lipid metabolism were associated with HCC occurrence. This population is characterized by a dramatic decrease in HCC incidence following SVR. It has been suggested that the residual oncogenic risk in these patients could be driven by the associated comorbidities, as highlighted by the high rates of excessive alcohol consumption and/or the presence of multiple features of the metabolic syndrome in our prospective cohorts.[2]Nahon P. Bamba-Funck J. Layese R. Trepo E. Zucman-Rossi J. Cagnot C. et al.Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis.J Hepatol. 2022 Nov 22; (S0168-8278(22)03294-9. https://dx.doi.org/10.1016/j.jhep.2022.11.003)Abstract Full Text Full Text PDF Scopus (9) Google Scholar Consequently, it is tempting to speculate that beyond the influence of ancestry, HCC genetic traits might exert a different impact according to the cause of the underlying CLD, which is also known to promote the development of different HCC subtypes. For example, alcohol-related HCCs are enriched in CTNNB1 somatic mutations, the gene coding for β-catenin.[6]Schulze K. Imbeaud S. Letouze E. Alexandrov L.B. Calderaro J. Rebouissou S. et al.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Nat Genet. 2015; 47: 505-511Crossref PubMed Scopus (1136) Google Scholar In further analyses, the WNT3A-WNT9A rs708113[T] protective allele identified by our GWAs was associated with a lower prevalence of CTNNB1-mutated HCC in patients with ALD, suggesting potential complex gene-alcohol interactions. It can be anticipated that HCC risk stratification aimed at refining HCC surveillance in patients with CLD will ultimately be developed in countries where antiviral therapies are widely implemented, and the relative weight of ALD and/or NAFLD are increasing. In this context, “universal” HCC scoring systems based on routine parameters have been developed with success in Asian and European populations.[7]Fan R. Papatheodoridis G. Sun J. Innes H. Toyoda H. Xie Q. et al.aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.J Hepatol. 2020; 73: 1368-1378Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar The predictive ability of polygenic risk scores (PRSs) highly depends on the population used for its development. Accordingly, it has been shown that PRSs developed from GWASs of individuals of European ancestry are several times less accurate in individuals of other ancestries.[8]Martin A.R. Kanai M. Kamatani Y. Okada Y. Neale B.M. Daly M.J. Clinical use of current polygenic risk scores may exacerbate health disparities.Nat Genet. 2019; 51: 584-591Crossref PubMed Scopus (1081) Google Scholar Multi-ancestry GWASs are key to maximizing genetic discovery but will also reduce health disparities[9]Wojcik G.L. Graff M. Nishimura K.K. Tao R. Haessler J. Gignoux C.R. et al.Genetic analyses of diverse populations improves discovery for complex traits.Nature. 2019; 570: 514-518Crossref PubMed Scopus (437) Google Scholar through the development of more ancestry-tailored PRSs. Including genetic variants relevant to diverse populations will improve the predictive value and thus generalizability of PRSs that should gather genetic and environmental information.[10]Wand H. Lambert S.A. Tamburro C. Iacocca M.A. O'Sullivan J.W. Sillari C. et al.Improving reporting standards for polygenic scores in risk prediction studies.Nature. 2021; 591: 211-219Crossref PubMed Scopus (171) Google Scholar Future steps will require the identification of novel genetic variants and their subsequent validation in longitudinal cohorts of well-phenotyped patients, reflecting the evolving epidemiological trends in HCC in Eastern and Western populations. This study received no funding from any organization or government. No potential conflicts of interest should be disclosed in this study. Please refer to the accompanying ICMJE disclosure forms for further details. PN and ET drafted and revised the manuscript. The following are the supplementary data to this article: Download .pdf (.74 MB) Help with pdf files Multimedia component 1