title: Identification of new SNPs associated with severe toxicity to capecitabine.
abstract: Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pellicer
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: Xandra
authors.initials: X
authors.lastname: García-González
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: María I
authors.initials: MI
authors.lastname: García
authors.affiliation: Hospital Universitario Doce de Octubre, Instituto de Investigación Sanitaria Hospital Doce de Octubre, Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Robles
authors.affiliation: Hospital Universitario Doce de Octubre, Instituto de Investigación Sanitaria Hospital Doce de Octubre, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Grávalos
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Alfonso
authors.affiliation: Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pachón
authors.affiliation: Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Longo
authors.affiliation: Hospital Universitario La Paz, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Martínez
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Blanco
authors.affiliation: Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Iglesias
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Sanjurjo
authors.affiliation: Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. Electronic address: luis.lopez@iisgm.com.
authors.forename: Luis A
authors.initials: LA
authors.lastname: López-Fernández
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D000069287:Capecitabine / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D003430:Cross-Sectional Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine
keywords: 5-fluorouracil (PubChem CID: 3385); Capecitabine; Capecitabine (PubChem CID: 60953); Drug adverse reaction; Pharmacogenetics; Tag SNPs