Impact of genetic polymorphisms on treatment efficacy in patients with hepatocellular carcinoma

Introduction Single nucleotide polymorphisms (SNPs) affecting the PNPLA3 (rs738409), TM6SF2 (rs58542926) and MBOAT7 (rs641738) genes alter liver disease progression and hepatocellular carcinoma (HCC) development via modulation of hepatic lipid homeostasis. The IL-7 (rs16906115) SNP improved response but increased the incidence of immune-related adverse events (irAEs) in patients with melanoma treated with immunotherapy (IT). The importance of the four SNPs in patients with HCC undergoing systemic treatment is unknown.

Material and Methods We included HCC patients treated with systemic therapy at two institutions (Medical University of Vienna and University Medical Center Hamburg-Eppendorf). SNP-genotyping was performed using real-time PCR systems following the manufacturer’s recommendations.

Results We included 116 patients (male:n=91, 78.4%) with a median age of 70.1 (IQR: 61.7-74.9) years. While the majority of patients (n=67, 56.3%) received IT (atezolizumab/bevacizumab:n=52, 77.6%), 49 (42.2%) patients underwent sorafenib treatment. Observed allele frequencies (wild-type/heterozygous/homozygous variants) were: PNPLA3 (28.4%/56.0%/15.5%), MBOAT7 (32.8%/50.9%/16.4%), TM6SF2 (71.6%/27.6%/0.9%), and IL-7 (84.5%/14.7%/0.9%). When calculating dominant models (i.e., grouping homozygous and heterozygous variants), the PNPLA3 (HR:1.02 (95%CI:0.62-1.69); p=0.938), TM6SF2 (HR:0.99 (95%CI:0.60-1.62);p=0.956) and MBOAT7 (HR:0.98 (95%CI:0.60-1.61);p=0.939) SNPs were not associated with overall survival (OS). The IL-7 SNP was also not associated with OS in the overall cohort (HR:1.45 (95%CI:0.81-2.64);p=0.211), however there was a tendency towards improved OS in the non-wildtype IT-cohort (HR:0.79 (95%CI:0.28-2.27);p=0.662) and worse OS in the sorafenib-cohort (HR:2.16 (95%CI:1.03-4.56);p=0.042). Interestingly, all of the 7 IL-7 non-wildtype IT-treated patients achieved radiological disease control. Overall, 37.3% of IT-patients experienced irAEs. The rate of irAEs was comparable between patients with vs. without harbouring an IL-7 risk allele.

Conclusion PNPLA3, MBOAT7 and TM6SF2 risk alleles are commonly found in patients with HCC undergoing systemic treatment, however, their presence was not associated with worse OS. The IL-7 rs16906115 risk allele is very rare; however, it may affect outcomes and should therefore be evaluated in a larger cohort of patients.

Publication History

Article published online:
13 May 2025