2026-08-29T13:36:24Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/174982024-11-29T16:06:31Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Leandro-García, Luis J author Leskelä, Susanna author Jara, Carlos author Gréen, Henrik author Avall-Lundqvist, Elisabeth author Wheeler, Heather E author Dolan, M Eileen author Inglada-Perez, Lucia author Maliszewska, Agnieszka author de Cubas, Aguirre A author Comino-Méndez, Iñaki author Mancikova, Veronika author Cascón, Alberto author Rodríguez-Antona, Cristina author Robledo Batanero, Mercedes author 2012-08-15 PURPOSE Peripheral neuropathy is the dose-limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat several solid tumors such as breast, lung, and ovary. The cytotoxic effect of paclitaxel is mediated through β-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in β-tubulin genes. EXPERIMENTAL DESIGN We measured variation in gene expression of three β-tubulin isotypes (I, IVb, and IIa) in lymphocytes from 100 healthy volunteers, sequenced the promoter region to identify polymorphisms putatively influencing gene expression and assessed the transcription rate of the identified variants using luciferase assays. To determine whether the identified regulatory polymorphisms were associated with paclitaxel neurotoxicity, we genotyped them in 214 patients treated with paclitaxel. In addition, paclitaxel-induced cytotoxicity in lymphoblastoid cell lines was compared with β-tubulin expression as measured by Affymetrix exon array. RESULTS We found a 63-fold variation in β-tubulin IIa gene (TUBB2A) mRNA content and three polymorphisms located at -101, -112, and -157 in TUBB2A promoter correlated with increased mRNA levels. The -101 and -112 variants, in total linkage disequilibrium, conferred TUBB2A increased transcription rate. Furthermore, these variants protected from paclitaxel-induced peripheral neuropathy [HR, 0.62; 95% confidence interval (CI), 0.42-0.93; P = 0.021, multivariable analysis]. In addition, an inverse correlation between TUBB2A and paclitaxel-induced apoptosis (P = 0.001) in lymphoblastoid cell lines further supported that higher TUBB2A gene expression conferred lower paclitaxel sensitivity. CONCLUSIONS This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a β-tubulin gene. Clin Cancer Res . 2012;18(16):4441-8. 10.1158/1078-0432.CCR-12-1221 1557-3265 Clinical cancer research : an official journal of the American Association for Cancer Research 22718863 http://hdl.handle.net/20.500.12105/17498 Regulatory polymorphisms in β-tubulin IIa are associated with paclitaxel-induced peripheral neuropathy.