Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma

• Published in: International journal of molecular sciences 2024-02, Vol.25 (4), p.2197
• Main Authors: Giannitrapani, Lydia, Di Gaudio, Francesca, Cervello, Melchiorre, Scionti, Francesca, Ciliberto, Domenico, Staropoli, Nicoletta, Agapito, Giuseppe, Cannataro, Mario, Tassone, Pierfrancesco, Tagliaferri, Pierosandro, Seidita, Aurelio, Soresi, Maurizio, Affronti, Marco, Bertino, Gaetano, Russello, Maurizio, Ciriminna, Rosaria, Lino, Claudia, Spinnato, Francesca, Verderame, Francesco, Augello, Giuseppa, Arbitrio, Mariamena
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Antineoplastic Agents - therapeutic use; Biological markers; Biomarkers; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Care and treatment; Classification; Datasets; Dehydrogenases; Ethylenediaminetetraacetic acid; Genes; Genetic Markers; Genotype & phenotype; Hepatoma; Humans; Inhibitor drugs; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Machine learning; Medical prognosis; Medical research; Medicine, Experimental; Niacinamide - therapeutic use; Patients; Phenylurea Compounds - therapeutic use; Physiological aspects; Single nucleotide polymorphisms; Sorafenib - pharmacology; Sorafenib - therapeutic use; Targeted cancer therapy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25042197

The identification of biomarkers for predicting inter-individual sorafenib response variability could allow hepatocellular carcinoma (HCC) patient stratification. SNPs in angiogenesis- and drug absorption, distribution, metabolism, and excretion (ADME)-related genes were evaluated to identify new potential predictive biomarkers of sorafenib response in HCC patients. Five known SNPs in angiogenesis-related genes, including , , , , and , were investigated in 34 HCC patients (9 sorafenib responders and 25 non-responders). A subgroup of 23 patients was genotyped for SNPs in ADME genes. A machine learning classifier method was used to discover classification rules for our dataset. We found that only the (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in (rs6811453), (rs10008281), (rs11401), (rs7905939), (rs2297595 and rs1801265), (rs2020863), and (rs149738, rs171248, and rs183574) significantly associated with sorafenib response. We have identified a genetic signature of predictive response that could permit non-responder/responder patient stratification. Angiogenesis- and ADME-related genes correlation was confirmed by cumulative genetic risk score and network and pathway enrichment analysis. Our findings provide a proof of concept that needs further validation in follow-up studies for HCC patient stratification for sorafenib prescription.