title: Functional PTGS2 polymorphism-based models as novel predictive markers in metastatic renal cell carcinoma patients receiving first-line sunitinib.
abstract: Sunitinib is the currently standard treatment for metastatic renal cell carcinoma (mRCC). Multiple candidate predictive biomarkers for sunitinib response have been evaluated but none of them has been implemented in the clinic yet. The aim of this study was to analyze single nucleotide polymorphisms (SNPs) in genes linked to mode of action of sunitinib and immune response as biomarkers for mRCC. This is a multicenter, prospective and observational study involving 20 hospitals. Seventy-five mRCC patients treated with sunitinib as first line were used to assess the impact of 63 SNPs in 31 candidate genes on clinical outcome. rs2243250 (IL4) and rs5275 (PTGS2) were found to be significantly associated with shorter cancer-specific survival (CSS). Moreover, allele C (rs5275) was associated with higher PTGS2 expression level confirming its functional role. Combination of rs5275 and rs7651265 or rs2243250 for progression free survival (PFS) or CSS, respectively, was a more valuable predictive biomarker remaining significant after correction for multiple testing. It is the first time that association of rs5275 with survival in mRCC patients is described. Two-SNP models containing this functional variant may serve as more predictive biomarkers for sunitinib and could suppose a clinically relevant tool to improve the mRCC patient management.
authors.affiliation: Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Arancha
authors.initials: A
authors.lastname: Cebrián
authors.affiliation: Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gómez Del Pulgar
authors.affiliation: Reina Sofía University Hospital, Córdoba, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Méndez-Vidal
authors.affiliation: Virgen de la Arrixaca University Hospital, Murcia, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Gonzálvez
authors.affiliation: Complejo Hospitalario de Navarra, Pamplona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lainez
authors.affiliation: 12 de Octubre University Hospital, Madrid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Castellano
authors.affiliation: Virgen de la Salud University Hospital, Toledo, Spain.
authors.forename: Iciar
authors.initials: I
authors.lastname: García-Carbonero
authors.affiliation: Central University Hospital of Asturias, Oviedo, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Esteban
authors.affiliation: Virgen de la Victoria University Hospital, Málaga, Spain.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Sáez
authors.affiliation: Hospital Costa del Sol, Marbella, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Villatoro
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Suárez
authors.affiliation: Ramon y Cajal University Hospital, Madrid, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.affiliation: Hospital Provincial de Castellón, Castellón, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Munárriz-Ferrándiz
authors.affiliation: Hospital de Donostia, San Sebastian, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Basterrechea
authors.affiliation: Insular de Gran Canaria University Hospital, Islas Canarias, Spain.
authors.forename: Mirta
authors.initials: M
authors.lastname: García-Alonso
authors.affiliation: Clinico San Carlos University Hospital, Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: González-Larriba
authors.affiliation: Virgen del Rocío University Hospital, Sevilla, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Perez-Valderrama
authors.affiliation: Canarias University Hospital, Santa Cruz de Tenerife, Islas Canarias, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Cruz-Jurado
authors.affiliation: Son Espases University Hospital, Palma de Mallorca, Spain.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: González Del Alba
authors.affiliation: Fuenlabrada University Hospital, Fuenlabrada, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Moreno
authors.affiliation: La Fe University Hospital, Valencia, Spain.
authors.forename: Gaspar
authors.initials: G
authors.lastname: Reynés
authors.affiliation: Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Remírez
authors.affiliation: Center for Applied Medical Research, Pamplona, Spain.
authors.forename: Valentina
authors.initials: V
authors.lastname: Boni
authors.affiliation: Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Mahillo-Fernández
authors.affiliation: Trial Form Support, Madrid, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Martin
authors.affiliation: Pfizer Oncology, Madrid, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Viqueira
authors.affiliation: Fundación Jiménez Díaz University Hospital, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Foncillas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D000077210:Sunitinib; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000077210:Sunitinib