Topoisomerase I (TOP-I) mutations have been shown to be correlated to irinotecan resistance in vitro. However, the prevalence of TOP-I germline mutations has yet to be systematically elucidated. On the other hand, polymorphisms of UGT1A1 have been shown to be associated with CPT-11 toxicity in clinical situations. The primary aim of this study was to investigate the prevalence of mutations in the TOP-I exons associated with CPT-11 resistance, including untreated cancer tissue. A secondary aim was to confirm the less frequent UGT1A1*28 and more frequent UGT1A1*6 in individuals of Asian descent compared to Caucasians and individuals of African descent. The prevalence of 5 reported TOP-I mutations in exons was investigated in volunteers (n=236) using DNA sequencing of the PCR products. The prevalence of TOP-I mutations in untreated lung cancer tissues (n=16) was also investigated. Additionally, 3 UGT1A1 polymorphisms, UGT1A1*6, *27 and *28, were investigated in volunteers (n=126). There were no mutations of TOP-I in any of the 236 subjects or in the untreated lung tissues. Among 128 subjects, the distribution of homozygous polymorphisms of UGT1A1 was: UGT1A1*28 in 3 (2.4%) and UGT1A1*6 in 4 (3.2%) subjects, and co-occurrence of heterozygous polymorphisms for both UGT1A1*6 and UGT1A1*28 in 4 (3.2%) subjects, and for UGT1A1*27 and UGT1A1*28 in 1 subject (0.8%). The Hardy-Weinberg deviation test showed there was no significant deviation from the equilibrium, and the association analysis indicated no significant linkage between UGT1A1*6 and UGT1A1*28. In conclusion, TOP-I genetic mutations correlated to CPT-11 resistance were not detected in any of the subjects and untreated lung cancer tissues. Less frequent UGT1A1*28 and more frequent UGT1A1*6 were confirmed in East Asian individuals compared to Caucasians and individuals of African descent. Linkage disequilibrium was not detected between UGT1A1*6 and UGT1A1*28.

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