Regulatory Polymorphisms in beta-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy
2012 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, no 16, 4441-4448 p.Article in journal (Refereed) Published
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 beta-tubulin binding in the cellular microtubules. In this study, we investigated the association between paclitaxel neurotoxicity risk and regulatory genetic variants in beta-tubulin genes. less thanbrgreater than less thanbrgreater thanExperimental Design: We measured variation in gene expression of three beta-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 beta-tubulin expression as measured by Affymetrix exon array. less thanbrgreater than less thanbrgreater thanResults: We found a 63-fold variation in beta-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. less thanbrgreater than less thanbrgreater thanConclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene.
Place, publisher, year, edition, pages
American Association for Cancer Research , 2012. Vol. 18, no 16, 4441-4448 p.
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-82068DOI: 10.1158/1078-0432.CCR-12-1221ISI: 000307504200027OAI: oai:DiVA.org:liu-82068DiVA: diva2:557972
Funding Agencies|Spanish Ministry of Science and Innovation|SAF2009-08307|Spanish Ministry of Economy and Competitiveness||NIH/NIGMS Pharmacogenomics of Anticancer Agents|U01GM61393|NIH/NCI|T32CA09594|Swedish Cancer Society||Swedish Research Council||FIS fellowship|FI08/00375|2012-10-012012-09-282015-03-27