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Vol. 1, 215-225, January 2002     Molecular Cancer Therapeutics
© 2002 American Association for Cancer Research

Conservation of the Class I ß-Tubulin Gene in Human Populations and Lack of Mutations in Lung Cancers and Paclitaxel-resistant Ovarian Cancers1

Sanja Sale, Raphael Sung, Peidong Shen, Kristine Yu, Yan Wang, George E. Duran, Jong-Hyeok Kim, Tito Fojo, Peter J. Oefner and Branimir I. Sikic2

Stanford University School of Medicine, Stanford, California 94305-5151 [S. S., Y. W., G. E. D., B. I. S.]; Stanford Genome Technology Center, Palo Alto, California 94306 [R. S., P. S., K. Y., P. J. O.]; and Medicine Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland 20892 [T. F., J-H. K.]

The goal of this study was to determine the prevalence of sequence variants in the class I ß-tubulin (clone m40) gene and their occurrence in human tumors and cancer cell lines. DNA was isolated from 93 control individuals representing a wide variety of ethnicities, 49 paclitaxel-naive specimens (16 ovarian cancers, 17 non-small cell lung cancers, and 16 ovarian cancer cell lines), and 30 paclitaxel-resistant specimens (9 ovarian cancers, 9 ovarian cancer cell lines, and 12 ovarian cancer xenografts in nude mice). Denaturing high-performance liquid chromatography and direct sequence analysis detected two silent polymorphisms in exon 4, Leu217Leu (CTG/CTA) and Gly400Gly (GGC/GGT), with minor allele frequencies of 17 and 0.5%, respectively. Five nucleotide substitutions and one single-base deletion were detected in introns 1, 2, and 3 and in the 3' untranslated region. Analysis of 49 paclitaxel-naive and 30 paclitaxel-resistant specimens revealed no additional polymorphisms in the coding region. In addition, no amino acid replacements were found in chimpanzee, gorilla, and orangutan in comparison to human. Our data demonstrate a very high degree of sequence conservation in class I ß-tubulin, suggesting that all residues are important in tubulin structure and function. Individual variation in response to treatment with paclitaxel is not likely to be caused by genetic variations in the ß-tubulin drug target. Moreover, acquired mutations in class I ß-tubulin are unlikely to be a clinically relevant cause of drug resistance.




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Copyright © 2002 by the American Association for Cancer Research.