title: Sunitinib-induced hypertension in CYP3A4 rs4646437 A-allele carriers with metastatic renal cell carcinoma.
abstract: The single nucleotide polymorphism (SNP) rs4646437G>A in CYP3A4 was suggested to be related to sunitinib toxicity. Our objective was to perform an in-depth investigation of the association between this SNP and sunitinib toxicity and efficacy using a large cohort of metastatic renal cell carcinoma (mRCC) patients. We collected DNA and clinical information of mRCC patients treated with sunitinib. SNP rs4646437 in CYP3A4 was tested for associations with toxicity using logistic regression. Cox regression modeling was used for association analysis of rs4646437 with progression-free survival (PFS) and overall survival (OS). In a total of 287 patients, the A-allele of CYP3A4 rs4646437 was associated with an increased risk for hypertension (odds ratio=2.4, 95% confidence interval: 1.1-5.2, P=0.021) and showed no significant association with PFS or OS. In conclusion, hypertension is more likely to occur in A-allele carriers of the CYP3A4 rs4646437 variant in our cohort of mRCC patients treated with sunitinib.
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.|Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Diekstra
authors.affiliation: Department of Clinical Pharmacy, Hospital Universitario Cruces, Barakaldo, Bizkaia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Belaustegui
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.|Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Swen
authors.affiliation: Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.|Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Boven
authors.affiliation: Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain.|Spanish Oncology Genitourinary Group, Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.|Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.|Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: R H
authors.initials: RH
authors.lastname: Mathijssen
authors.affiliation: Spanish Oncology Genitourinary Group, Madrid, Spain.|Oncology Unit, Clara Campal Comprehensive Cancer Center, Madrid, Spain.
authors.forename: J
authors.initials: J
authors.lastname: García-Donas
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center, Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases, Madrid, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.affiliation: Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: B I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.|Dutch Working Group Focusing on Genotype-related Sunitinib-induced Toxicity (SUTOX Consortium), Leiden, The Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Guchelaar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D016009:Chi-Square Distribution; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005060:Europe; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D007211:Indoles / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016017:Odds Ratio; D009820:Ohio; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011758:Pyrroles / Q000009:adverse effects*; D012189:Retrospective Studies; D012307:Risk Factors; D000077210:Sunitinib; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077210:Sunitinib
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