Fukui Tomoya, Mitsufuji Hisashi, Kubota Masaru, Inaoka Hidenori, Hirose Minoru, Iwabuchi Keiichi, Masuda Noriyuki, Kobayashi Hirosuke
Department of Respiratory Medicine, School of Medicine, Kitasato University, Kanagawa 252-0373, Japan.
Oncol Lett. 2011 Sep 1;2(5):923-928. doi: 10.3892/ol.2011.346. Epub 2011 Jul 5.
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 UGT1A128 and more frequent UGT1A16 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, UGT1A16, 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: UGT1A128 in 3 (2.4%) and UGT1A16 in 4 (3.2%) subjects, and co-occurrence of heterozygous polymorphisms for both UGT1A16 and UGT1A128 in 4 (3.2%) subjects, and for UGT1A127 and UGT1A128 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 UGT1A16 and UGT1A128. 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 UGT1A128 and more frequent UGT1A16 were confirmed in East Asian individuals compared to Caucasians and individuals of African descent. Linkage disequilibrium was not detected between UGT1A16 and UGT1A1*28.
拓扑异构酶I（TOP-I）突变已被证明在体外与伊立替康耐药性相关。然而，TOP-I种系突变的患病率尚未得到系统阐明。另一方面，UGT1A1的多态性已被证明在临床情况下与CPT-11毒性相关。本研究的主要目的是调查与CPT-11耐药相关的TOP-I外显子突变的患病率，包括未经治疗的癌组织。次要目的是证实与白种人和非洲裔个体相比，亚洲裔个体中UGT1A128的频率较低，UGT1A16的频率较高。使用PCR产物的DNA测序在志愿者（n = 236）中调查了5种已报道的外显子TOP-I突变的患病率。还调查了未经治疗的肺癌组织（n = 16）中TOP-I突变的患病率。此外，在志愿者（n = 126）中调查了3种UGT1A1多态性，即UGT1A16、27和28。在236名受试者中的任何一名或未经治疗的肺组织中均未检测到TOP-I突变。在128名受试者中，UGT1A1纯合多态性的分布为：3名受试者（2.4%）为UGT1A128，4名受试者（3.2%）为UGT1A16，4名受试者（3.2%）同时存在UGT1A16和UGT1A128的杂合多态性，1名受试者（0.8%）同时存在UGT1A127和UGT1A128的杂合多态性。Hardy-Weinberg偏离检验表明与平衡无显著偏离，关联分析表明UGT1A16和UGT1A128之间无显著连锁。总之，在任何受试者和未经治疗的肺癌组织中均未检测到与CPT-11耐药相关的TOP-I基因突变。与白种人和非洲裔个体相比，东亚个体中UGT1A128的频率较低，UGT1A16的频率较高。未检测到UGT1A16和UGT1A1*28之间的连锁不平衡。
