Genetic Biomarkers of Sorafenib Response in Patients with Hepatocellular Carcinoma

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 VEGF-A, VEGF-C, HIF-1a, ANGPT2, and NOS3, 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 VEGF-A (rs2010963) C allele and CC genotype were significantly associated with sorafenib response. ADME-related gene analysis identified 10 polymorphic variants in ADH1A (rs6811453), ADH6 (rs10008281), SULT1A2/CCDC101 (rs11401), CYP26A1 (rs7905939), DPYD (rs2297595 and rs1801265), FMO2 (rs2020863), and SLC22A14 (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.

[1]  Bo Li,et al.  Efficacy and safety of lenvatinib versus sorafenib in first-line treatment of advanced hepatocellular carcinoma: A meta-analysis , 2022, Frontiers in Oncology.

[2]  M. Cannataro,et al.  A statistical network pre-processing method to improve relevance and significance of gene lists in microarray gene expression studies , 2022, BMC Bioinformatics.

[3]  Yunxing Wang,et al.  CYP26A1 Is a Novel Cancer Biomarker of Pancreatic Carcinoma: Evidence from Integration Analysis and In Vitro Experiments , 2022, Disease markers.

[4]  M. Cannataro,et al.  Risk Alleles for Multiple Myeloma Susceptibility in ADME Genes , 2022, Cells.

[5]  Mario Cannataro,et al.  Using BioPAX-Parser (BiP) to enrich lists of genes or proteins with pathway data , 2021, BMC Bioinformatics.

[6]  Y. Liu,et al.  Prognostic SLC family genes promote cell proliferation, migration, and invasion in hepatocellular carcinoma. , 2021, Acta biochimica et biophysica Sinica.

[7]  T. Agarwal,et al.  Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches , 2021, Cancer cell international.

[8]  P. Tassone,et al.  Pharmacogenomics Biomarker Discovery and Validation for Translation in Clinical Practice , 2020, Clinical and translational science.

[9]  Hongjuan You,et al.  Prognostic implications of alcohol dehydrogenases in hepatocellular carcinoma , 2020, BMC Cancer.

[10]  Yulei N. Wang,et al.  Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. , 2020, The New England journal of medicine.

[11]  V. Zagonel,et al.  Association of NOS3 and ANGPT2 Gene Polymorphisms with Survival in Patients with Hepatocellular Carcinoma Receiving Sorafenib: Results of the Multicenter Prospective INNOVATE Study , 2020, Clinical Cancer Research.

[12]  Stephen L. Abrams,et al.  New landscapes and horizons in hepatocellular carcinoma therapy , 2020, Aging.

[13]  P. Ulivi,et al.  Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE-2 Study , 2020, Targeted Oncology.

[14]  Igor Jurisica,et al.  pathDIP 4: an extended pathway annotations and enrichment analysis resource for human, model organisms and domesticated species , 2019, Nucleic Acids Res..

[15]  A. Dimberg,et al.  Tumor angiogenesis: causes, consequences, challenges and opportunities , 2019, Cellular and Molecular Life Sciences.

[16]  Mario Cannataro,et al.  Polymorphic Variants in NR1I3 and UGT2B7 Predict Taxane Neurotoxicity and Have Prognostic Relevance in Patients With Breast Cancer: A Case‐Control Study , 2019, Clinical pharmacology and therapeutics.

[17]  Weidong Zhang,et al.  Prediction model for the efficacy of folic acid therapy on hyperhomocysteinaemia based on genetic risk score methods , 2019, British Journal of Nutrition.

[18]  Wei Zhang,et al.  Increased expression of SLC46A3 to oppose the progression of hepatocellular carcinoma and its effect on sorafenib therapy. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[19]  M. Montico,et al.  A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First‐Line Exemestane: Results From a Prospective Study , 2019, Clinical breast cancer.

[20]  Igor Jurisica,et al.  IID 2018 update: context-specific physical protein–protein interactions in human, model organisms and domesticated species , 2018, Nucleic Acids Res..

[21]  M. Canale,et al.  Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers? , 2018, World journal of gastroenterology.

[22]  R. Cantello,et al.  Using a Genetic Risk Score Approach to Predict Headache Response to Triptans in Migraine Without Aura , 2018, Journal of clinical pharmacology.

[23]  E. Scarpi,et al.  Multicenter prospective study of angiogenesis polymorphism validation in HCC patients treated with sorafenib. An INNOVATE study protocol , 2018, Tumori.

[24]  Giuseppe Agapito,et al.  Genetic variants associated with Fabry disease progression despite enzyme replacement therapy , 2017, Oncotarget.

[25]  R. Altman,et al.  PharmGKB summary: sorafenib pathways , 2017, Pharmacogenetics and genomics.

[26]  J. Marin,et al.  The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma , 2016, Zeitschrift für Gastroenterologie.

[27]  J. Martinez-Picado,et al.  Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions , 2016, Front. Pharmacol..

[28]  Mario Cannataro,et al.  DMET™ (Drug Metabolism Enzymes and Transporters): a pharmacogenomic platform for precision medicine , 2016, Oncotarget.

[29]  O. Nanni,et al.  eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: final results of the ePHAS study , 2016, Oncotarget.

[30]  P. Ulivi,et al.  Angiogenesis polymorphisms profile in the prediction of clinical outcome of advanced HCC patients receiving sorafenib: Combined analysis of VEGF and HIF-1α—Final results of the ALICE-2 study. , 2016 .

[31]  K. Inui,et al.  Management of dose variability and side effects for individualized cancer pharmacotherapy with tyrosine kinase inhibitors. , 2015, Pharmacology & therapeutics.

[32]  M. Osanai,et al.  The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells. , 2015, Oncology reports.

[33]  Chung-Yen Lin,et al.  cytoHubba: identifying hub objects and sub-networks from complex interactome , 2014, BMC Systems Biology.

[34]  M. Osanai,et al.  Increased expression of the retinoic acid-metabolizing enzyme CYP26A1 during the progression of cervical squamous neoplasia and head and neck cancer , 2014, BMC Research Notes.

[35]  E. Hatano,et al.  Biological and clinical implications of retinoic acid-responsive genes in human hepatocellular carcinoma cells. , 2013, Journal of hepatology.

[36]  O. Briz,et al.  Expression of SLC22A1 variants may affect the response of hepatocellular carcinoma and cholangiocarcinoma to sorafenib , 2013, Hepatology.

[37]  F. Abu-Hijleh,et al.  The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease , 2012, European journal of haematology.

[38]  J. Bruix,et al.  Management of hepatocellular carcinoma: An update , 2011, Hepatology.

[39]  A. Leutenegger,et al.  Genetics of VEGF Serum Variation in Human Isolated Populations of Cilento: Importance of VEGF Polymorphisms , 2011, PloS one.

[40]  Riccardo Lencioni,et al.  Modified RECIST (mRECIST) Assessment for Hepatocellular Carcinoma , 2010, Seminars in liver disease.

[41]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[42]  S. Wilhelm,et al.  Discovery and development of sorafenib: a multikinase inhibitor for treating cancer , 2006, Nature Reviews Drug Discovery.

[43]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[44]  R. Lotan.  Retinoids as modulators of tumor cells invasion and metastasis. , 1991, Seminars in cancer biology.

[45]  P. Tagliaferri,et al.  Ethical Perspectives on Pharmacogenomic Profiling , 2021, Reference Module in Biomedical Sciences.

[46]  Riccardo Lencioni,et al.  EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. , 2012, Journal of hepatology.

[47]  S. Erlinger,et al.  European Association for the Study of the Liver , 2006 .

[48]  Pacific Symposium on Biocomputing 12:76-87(2007) DISCOVERY OF PROTEIN INTERACTION NETWORKS SHARED BY DISEASES # , 2022 .