enHanCCing knowledge of genetic factors in primary liver tumor
Authors: Jill Koshiol, Marcin Krawczyk
Journal: Hepatology (2024)

HCC, the most common primary liver tumor, is closely linked to cirrhosis, with an annual incidence reaching 6% among patients with cirrhosis.1 The risk of HCC arises from a complex interplay of external and inherited factors. Metabolic dysfunction–associated steatotic liver disease, alcohol-associated liver disease, and viral infections with HBV and HCV are recognized as the principal etiologies of liver conditions, markedly elevating the odds of developing HCC.2 Cirrhosis is an important intermediate step in the carcinogenesis process.3,4 However, the presence of cirrhosis does not universally result in HCC, underscoring the need for co-factors and the potential significance of genetic factors in disease development. Genome-wide association studies (GWAS) have emerged as a pivotal tool in understanding inherited predisposition to various diseases. This methodology involves analyzing thousands of genetic variants, predominantly single nucleotide polymorphisms, across large numbers of individuals to identify variants that are significantly associated with specific phenotypes, such as diseases or traits.5 In hepatology, GWAS has been instrumental in identifying variants associated with several chronic liver conditions,6 like fatty liver,7 liver cirrhosis,8 and notably HCC.9 GWAS studies have been crucial in detecting polymorphisms associated with increased risk of this liver malignancy in patients with various etiologies of chronic liver diseases. For instance, a study by Buch et al10 involving 1214 patients with alcohol-associated cirrhosis and HCC from 5 European countries (Austria, Italy, Germany, Switzerland, and UK) revealed that single nucleotide polymorphisms in Patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2, and telomerase reverse transcriptase significantly modulate the HCC risk in the European population. In the current issue of Hepatology, Manal et al11 present new data from an extensive study of North American patients with HCC, offering new insights into the genetic landscape of this malignancy. This GWAS of individuals from the European-descent populations involved a discovery set of 1872 HCC cases and 2907 controls and a validation set of 1200 HCC cases and 1832 controls. The authors identified associations with several previously established loci (22q13.31 in PNPLA3 [rs738409], 9q13.11 in transmembrane 6 superfamily 2 [rs58542926], and 5p15.33 in telomerase reverse transcriptase [rs2242652]), as well as identifying novel associations (19p13.11 in MAU2 sister chromatid cohesion factor [rs58489806] and 3p22.1 in Myelin-associated oligodendrocytic basic protein [rs9842969]), including one that was specific for HCV-related HCC (6p21.31 in major histocompatibility complex, class II, DQ beta 1 [rs9275224]) (Figure 1). The strongest findings were for previously identified variants in PNPLA3, which might increase the risk of HCC through liver steatosis and cirrhosis, and transmembrane 6 superfamily 2, which also influences liver fat and might promote hepatic inflammation. The inverse association with telomerase reverse transcriptase, a gene involved in maintaining telomere ends, is also consistent with previous studies from China and Europe. The novel association for the MAU2 sister chromatid cohesion factor variant is of particular interest given that eQTL colocalization suggests it as a candidate susceptibility gene. Interestingly, the MAU2 sister chromatid cohesion factor and Myelin-associated oligodendrocytic basic protein variants have been associated with lipid traits and lipid transport, respectively, highlighting the importance of the genetic underpinnings of liver steatosis in nonvirally associated HCC. Similarly, the association with the HLA-DQB1 in HCV-related HCC underscores the role of immune response in virally associated HCC.FIGURE 1: Overview of genetic variants linked to the increased risk of HCC in patients with nonviral (left side) and viral (right side) liver diseases, as reported by Manal et al.11 The x-axis presents the genes that have been found to be associated with HCC risk. The boxes above each gene present the OR with the middle line and the associated CIs with the upper and lower lines, indicating the likelihood of developing HCC among patients with each specific variant. Abbreviations: HLA-DQB1, major histocompatibility complex class II, DQ beta 1; MAU2, MAU2 sister chromatid cohesion factor; MOBP, myelin-associated oligodendrocytic basic protein; PNPLA3, patatin-like phospholipase domain-containing protein 3. TERT, telomerase reverse transcriptase; TM6SF2, transmembrane 6 superfamily 2.In this population, the estimated heritability of HCC was 22%,11 similar to some reports for other gastrointestinal cancers.12,13 The authors also found evidence that some individuals might be at particularly high risk of HCC due to gene-gene interaction. For example, individuals with homozygous PNPLA3 and telomerase reverse transcriptase variants had more than 5 times higher odds of developing HCC (OR: 6.5, 95% CI: 4.8–8.8) than those without these variants. One limitation of this study11 is that the controls tended to come from different institutions/sources than the cases, which could lead to questions about whether the differences in the populations from which the HCC cases arose might affect which polymorphisms were identified. However, all participants were required to have at least 80% alignment with ancestral European-descent populations. In addition, while there seemed to be some sociodemographic differences between cases and controls (eg, controls from the Southwest, Midwest, and Southeast tended to be younger than cases, and controls from the West, Midwest, Northeast, and Southeast included a higher proportion of females than cases), these differences seem unlikely to account for observed associations, particularly those replicating previous studies. This study represents an enormous effort with many investigators across numerous institutions, which is required for this type of research. To be effective, GWAS studies require extraordinarily large numbers. By making the effort to build a collaboration across multiple organizations, the authors were able to identify genetic variants that contribute to HCC risk, and these variants could be particularly important for identifying individuals at high risk who need added surveillance for HCC. This study is an excellent example of the kind of large-scale, multi-institutional collaboration that is needed to truly further our understanding of the genetic underpinnings of HCC. Despite the extensive effort involved in this multicentric study, even larger analyses are needed to provide stronger, clearer results. For example, in the current study, the top 10 loci presented in Table 1 purportedly had p < 5 × 10-8 in the discovery and validation sets, as well as the meta-analysis. However, only PNPLA3 and SAMM50 (which was later dropped as it was not associated with HCC independently from PNPLA3) had p < 5 × 10-8 in all 3 analyses. In fact, the major histocompatibility complex, class II, DQ beta 1 loci, while listed in Table 1, only had a p of 1.8 × 10-2 in the discovery analysis for HCC overall, although it was strongly associated with HCV-associated HCC. These inconsistencies demonstrate the need for ever-larger studies to better define genetic associations. What can we learn from this multicentric study? First of all, it reinforces the previous observations that genetic background modulates the risk of developing HCC.14 Although the costs of genotyping are now low, the idea of stratifying the patient's risk of developing progressive liver disease based on the genotyping of single nucleotide polymorphisms has not been widely accepted in clinical practice. Indeed, we still lack prospective studies that could, for instance, lead to new HCC screening strategies based on the patient's genetic risk profile. Conversely, we know that variants such as PNPLA3 p.I148M are responsible for progressive liver disease, leading to liver cirrhosis and liver tumors. Initial trials are already being performed to lower the risk of metabolic dysfunction–associated steatotic liver disease among carriers of the PNPLA3 p.148M risk allele.15 Four oligonucleotide-based PNPLA3-targeting trials are currently underway, one of which is a Phase II trial, with the reduction of liver scarring as a secondary end point, and the other 3 are Phase I trials.15 It is conceivable that successful ASO-based hepatic silencing of PNPLA3 might also reduce the risk of HCC among carriers of the risk genotype. Although not the focus of the current study, functional studies need to be undertaken to better understand whether the detected variants lead to biological changes that affect the risk of developing HCC, or whether they are in linkage disequilibrium with as-of-yet unknown functional variants. Elucidating the biological mechanisms involved in these genetic associations could help identify potential targets for early detection or treatment. Additionally, therapeutic strategies targeting genetic modulators of liver diseases beyond PNPLA3 are being developed,16 and their successful implementation might further contribute to a lower incidence of HCC among genetically predisposed individuals. Collectively, genetic analyses have advanced our understanding of the pathogenesis of various liver diseases, including primary tumors. Specifically, the study by Manal et al11 provides an important step forward towards enhancing our understanding of HCC. This new perspective, when integrated with the findings from other research groups, might lead to new strategies for cancer prevention and treatment, aiming to mitigate the burden associated with this liver malignancy.