Tumour SNPs Associated with Immune-Related Hepatitis in Patients with Melanoma Receiving Immune Checkpoint Inhibitors

Background and aims: Immune checkpoint inhibitors (ICIs) have significantly improved survival rates for patients with metastatic melanoma. However, these treatments can lead to immune-related adverse events (irAEs), including hepatitis. This exploratory study sought to identify tumour single-nucleotide polymorphisms (SNPs) associated with the risk of ICI-induced hepatitis in melanoma patients. Methods: The study cohort comprised 69 patients with malignant melanoma treated with ICIs at several hospitals in Madrid, Spain. DNA was extracted from formalin-fixed paraffin-embedded tumour biopsies and SNP genotyping was conducted using a MassARRAY platform. Results: Significant associations were found between hepatitis risk and 4 of the 20 SNPs examined. A possible risk effect was shown for the variant GABRP SNP alleles rs11743438 and rs11743735. Among patients homozygous for these variant alleles (v/v), significantly higher proportions developed hepatitis, 75% and 71.4%, respectively, compared to 32.8% and 21.4, respectively, not developing hepatitis (p = 0.046; p = 0.013). However, in the same genotype group comparisons, the RGMA SNP rs4778080 seemed to have a protective effect, as 100% of patients who developed hepatitis were not in the v/v group for this allele (p = 0.043). Additionally, in genotype group comparisons wt/wt versus wt/v + v/v, the PACRG SNP rs55733913 was also associated with a higher risk of ICI-induced hepatitis: 66.7% of patients with hepatitis versus 22.8% without hepatitis in genotype group wt/v + v/v (p = 0.041). Conclusions: This exploratory study identifies candidate tumour SNPs as possible biomarkers to predict the risk of ICI-induced hepatitis, warranting their validation in larger patient cohorts.