Regulatory polymorphisms in β-tubulin IIa are associated with paclitaxel-induced peripheral neuropathy.
OBJECTIVE
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.


METHODS
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.
Spanish National Cancer Research Center, Madrid, Spain.
Luis J
LJ
Leandro-García
Susanna
S
Leskelä
Carlos
C
Jara
Henrik
H
Gréen
Elisabeth
E
Avall-Lundqvist
Heather E
HE
Wheeler
M Eileen
ME
Dolan
Lucia
L
Inglada-Perez
Agnieszka
A
Maliszewska
Aguirre A
AA
de Cubas
Iñaki
I
Comino-Méndez
Veronika
V
Mancikova
Alberto
A
Cascón
Mercedes
M
Robledo
Cristina
C
Rodríguez-Antona
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics; D012306:Risk; D014404:Tubulin / Q000235:genetics*; D050257:Tubulin Modulators / Q000009:adverse effects* / Q000627:therapeutic use
D000972:Antineoplastic Agents, Phytogenic; D020033:Protein Isoforms; D014404:Tubulin; D050257:Tubulin Modulators; D017239:Paclitaxel