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Regulatory Polymorphisms in beta-Tubulin IIa Are Associated with Paclitaxel-Induced Peripheral Neuropathy
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- Leandro-Garcia, Luis J. (author)
- Spanish National Cancer Research Centre, Spain
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- Leskelä, Susanna (author)
- Spanish National Cancer Research Centre, Spain
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- Jara, Carlos (author)
- Fdn Hospital Alcorcon, Spain
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- Gréen, Henrik (author)
- Linköpings universitet,KTH,Genteknologi,Science for Life Laboratory, SciLifeLab,Klinisk farmakologi,Hälsouniversitetet
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- Åvall-Lundqvist, Elisabeth (author)
- Karolinska Institutet,Linköpings universitet,Avdelningen för kliniska vetenskaper,Hälsouniversitetet,Region Östergötland, Onkologiska kliniken US,Karolinska Institute, Sweden
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- Wheeler, Heather E. (author)
- University of Chicago, IL 60637 USA
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- Dolan, M. Eileen (author)
- University of Chicago, IL 60637 USA
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- Inglada-Perez, Lucia (author)
- Spanish National Cancer Research Centre, Spain CIBERER, Spain
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- Maliszewska, Agnieszka (author)
- Spanish National Cancer Research Centre, Spain
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- de Cubas, Aguirre A. (author)
- Spanish National Cancer Research Centre, Spain
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- Comino-Mendez, Inaki (author)
- Spanish National Cancer Research Centre, Spain
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- Mancikova, Veronika (author)
- Spanish National Cancer Research Centre, Spain
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- Cascon, Alberto (author)
- Spanish National Cancer Research Centre, Spain CIBERER, Spain
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- Robledo, Mercedes (author)
- Spanish National Cancer Research Centre, Spain CIBERER, Spain
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- Rodriguez-Antona, Cristina (author)
- Spanish National Cancer Research Centre, Spain CIBERER, Spain
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(creator_code:org_t)
- American Association for Cancer Research, 2012
- 2012
- English.
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In: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 18:16, s. 4441-4448
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- 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. Experimental 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. Results: 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. Conclusions: This is the first study showing that paclitaxel neuropathy risk is influenced by polymorphisms regulating the expression of a beta-tubulin gene.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Ovarian-Cancer
- Microtubule Dynamics
- Axonal-Transport
- Gene-Expression
- Breast-Cancer
- Tumor-Cells
- In-Vitro
- Taxol
- Agents
- Mutations
- MEDICINE
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Leandro-Garcia, ...
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Leskelä, Susanna
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Jara, Carlos
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Gréen, Henrik
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Åvall-Lundqvist, ...
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Wheeler, Heather ...
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Dolan, M. Eileen
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Inglada-Perez, L ...
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Maliszewska, Agn ...
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de Cubas, Aguirr ...
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Comino-Mendez, I ...
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Mancikova, Veron ...
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Cascon, Alberto
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Robledo, Mercede ...
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Rodriguez-Antona ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Clinical Cancer ...
- By the university
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Royal Institute of Technology
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Linköping University
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Karolinska Institutet