title: An exploratory association of polymorphisms in angiogenesis-related genes with susceptibility, clinical response and toxicity in gastrointestinal stromal tumors receiving sunitinib after imatinib failure.
abstract: The angiogenic pathway plays a pivotal role in tumor growth, invasiveness and metastasis. The most important actors in the angiogenic pathway are VEGFA and its receptors VEGFR1, 2 and 3. These genes are polymorphic, and the presence of single nucleotide polymorphisms may result in angiogenic deregulation. Herein, we hypothesized that germline variants may affect sunitinib efficacy (TTP and OS) and/or toxicity. Therefore, we investigated 19 polymorphisms, in four genes, in 54 GIST patients, treated with second-line sunitinib and 147 healthy controls. Through a multiple candidate gene approach, we also investigated, for the first time, any possible significant associations with GIST susceptibility and clinical pathological features. The most important result shows two associations between polymorphisms in VEGFR3 rs6877011 (CC vs. CG, OR 9.7, 95% CI 3.31-28.4; P < 0.001) and rs7709359 (AA+AG vs. GG, OR 5.01, 95% CI 1.33-18.8; P = 0.017) and TTP. Interestingly, the association between VEGFR3 rs6877011 and TTP maintained the significance after applying the Bonferroni correction for multiple testing (P = 0.017). We also highlighted the association with sunitinib-related toxicity; in particular, VEGFA polymorphism rs3025039 (CT+TT vs. CC, OR 15.3, 95% CI 2.2-102.1; P = 0.005) is associated with severe toxicity, with the presence of the variant T allele associated with a grade ≥3 AE. Because of the small sample size and large number of tests performed, we cannot ignore the possibility that some associations have been retrieved by chance. However, the influence of VEGF polymorphisms in angiogenesis is a hypothesis worthy of exploration in cellular models and confirmation in a sizeable cohort of patients.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Gloria
authors.identifier: http://orcid.org/0000-0002-7774-402X
authors.initials: G
authors.lastname: Ravegnini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Nannini
authors.affiliation: Unit of Epidemiology and Biostatistics, IRCCS, ISNB, Via Altura 3, 40139, Bologna, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Zenesini
authors.affiliation: Laboratory of Pre-Clinical and Translational Research Reference Cancer Center of Basilicata, Scientific Institute of Hospitalization and Treatment, Rionero in Vulture, Potenza, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Simeon
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Sammarini
authors.affiliation: "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Milena
authors.initials: M
authors.lastname: Urbini
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: Gatto
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Maristella
authors.initials: M
authors.lastname: Saponara
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Biasco
authors.affiliation: Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.|"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Pantaleo
authors.affiliation: Immunohematology and Blood Transfusion, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Venturoli
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Hrelia
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126, Bologna, Italy. s.angelini@unibo.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angelini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003710:Demography; D018450:Disease Progression; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000098:blood supply* / Q000188:drug therapy / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D007211:Indoles / Q000009:adverse effects*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011758:Pyrroles / Q000009:adverse effects*; D000077210:Sunitinib; D013997:Time Factors; D017211:Treatment Failure; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics; D055815:Young Adult
chemical_list: D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068877:Imatinib Mesylate; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; D000077210:Sunitinib
keywords: Angiogenesis; Clinical outcome; Clinical response; GIST; OS; Pharmacogenetics; Polymorphisms; SNP; Sunitinib; TTP; Toxicity; VEGF pathway; VEGFA; VEGFR1; VEGFR2; VEGFR3