Takeuchi S, Bartram C R, Wada M, Reiter A, Hatta Y, Seriu T, Lee E, Miller C W, Miyoshi I, Koeffler H P
Division of Hematology/Oncology, Cedars-Sinai Research Institute, University of California at Los Angeles School of Medicine 90048, USA.
Cancer Res. 1995 Nov 15;55(22):5377-82.
To identify the genetic events that may play an important role in leukemogenesis of childhood ALL, we report for the first time the allelotyping of childhood ALL. Twenty-four cases of childhood ALL were screened for loss of heterozygosity (LOH) using 101 highly polymorphic microsatellite markers, which are distributed among all autosomal chromosomes. For LOH analysis on both chromosomes 9 and 12, 54 childhood ALL samples were examined. The most frequent allelic loss was found on chromosomal arm 9p, where 20 of 50 (40%) informative samples showed LOH. Moreover, nearly 30% of samples that did not have either homozygous deletions or point mutations of the putative tumor suppressor genes CDKN2/INK4A/p16 and INK4B/p15 on chromosomal arm 9p had LOH at D9S171. Loss of chromosomal arm 12p was also frequent (26%). Mutational analysis suggested that the altered gene on 12p is not the cyclin-dependent kinase inhibitor p27/Kip1, which is also on 12p. Several other regions that had LOH included 1p, 4q, 5p, 6q, 7p, 8p, 9q, 10q, 13q, 17p, 17q, 18q, 19q, and 22q. Of 24 patients, 19 (79%) showed allelic loss on at least one chromosomal arm. Samples of two patients (8%) showed LOH on almost all chromosomes. Fractional allelic loss, calculated for each sample as the total number of chromosomal arms lost/total number of arms with information, showed a median value of 0.04 and a mean of 0.123 (range, 0 to 0.95). This fractional allelic loss is lower than those reported for many solid tumors. This analysis shows the extreme power of LOH analysis using microsatellite markers in childhood ALL.
为了确定可能在儿童急性淋巴细胞白血病（ALL）白血病发生过程中起重要作用的基因事件，我们首次报告了儿童ALL的等位基因分型情况。使用101个高度多态性微卫星标记对24例儿童ALL进行杂合性缺失（LOH）筛查，这些标记分布于所有常染色体上。为了对9号和12号染色体进行LOH分析，检测了54例儿童ALL样本。最常见的等位基因缺失发生在9号染色体短臂，在50个信息样本中有20个（40%）显示出LOH。此外，在9号染色体短臂上假定的肿瘤抑制基因CDKN2/INK4A/p16和INK4B/p15既没有纯合缺失也没有点突变的样本中，近30%在D9S171处存在LOH。12号染色体短臂的缺失也很常见（26%）。突变分析表明，12号染色体短臂上发生改变的基因不是同样位于12号染色体上的细胞周期蛋白依赖性激酶抑制剂p27/Kip1。其他几个存在LOH的区域包括1号染色体短臂、4号染色体长臂、5号染色体短臂、6号染色体长臂、7号染色体短臂、8号染色体短臂、9号染色体长臂、10号染色体长臂、13号染色体长臂、17号染色体短臂、17号染色体长臂、18号染色体长臂、19号染色体长臂和22号染色体长臂。在24例患者中，19例（79%）至少在一条染色体臂上显示出等位基因缺失。两名患者（8%）的样本在几乎所有染色体上都显示出LOH。每个样本的部分等位基因缺失计算为丢失的染色体臂总数/有信息的臂总数，其中位数为0.04，平均值为0.123（范围为0至0.95）。这种部分等位基因缺失低于许多实体瘤报告的数值。该分析显示了使用微卫星标记进行LOH分析在儿童ALL中的强大作用。
