Reato G, Basso G, Putti M C, Cignetti A, Guarini A, Foa R
Dipartimento di Scienze Biomediche ed Oncologia Umana, University of Turin, Italy.
Haematologica. 1998 May;83(5):403-7.
Genetic alterations, including genomic instability, represent possible steps towards a malignant transformation. One approach to delineate replication errors in cancer cells is to determine alterations of microsatellites that are short tandem repeat sequences dispersed throughout the human genome. We have investigated whether genomic instability may be a possible event in the leukemogenic process by evaluating the pattern of instability in 41 cases of childhood acute lymphoblastic leukemia (ALL).
Eighty-two samples of genomic DNA (41 at diagnosis and 41 at remission) were analyzed by PCR with microsatellite markers chosen on five different chromosomes (2, 10, 11, 13, 18) known to be frequently involved in tumors of various origins. Since deletions of the short arm of chromosome 12 are relatively common in children with ALL, we also analyzed one region flanked by the microsatellite marker D12S308 on 12p. This area encompasses a genetic locus which contains the putative suppressor gene KIP1.
A pattern of MI at one or two loci on different chromosomes could be documented in 4 of the 41 cases analyzed (9.7%). Three were common ALL and 1 was a T-ALL. One case showed two concomitant sites of instability, while 1 revealed two additional bands by using simultaneously microsatellite markers D2S123 and D18S58.
These results indicate that genetic instability of microsatellite repeat sequences occurs in a proportion of childhood ALL. Mismatched repair errors documented in hereditary and sporadic solid tumors may thus be involved in hematological malignancies. While in such cases the pattern of genomic instability appears indicative of a mutator phenotype and of a potential predisposition towards a leukemic transformation, other genomic loci close to cytogenetic and molecular alterations known to occur in ALL need to be investigated in depth in cases with an apparently non mutated phenotype.
包括基因组不稳定在内的基因改变是恶性转化的可能步骤。描绘癌细胞复制错误的一种方法是确定微卫星的改变，微卫星是遍布人类基因组的短串联重复序列。我们通过评估41例儿童急性淋巴细胞白血病（ALL）的不稳定模式，研究基因组不稳定是否可能是白血病发生过程中的一个事件。
用在5条不同染色体（2、10、11、13、18）上选择的微卫星标记进行PCR分析82份基因组DNA样本（41份诊断时样本和41份缓解时样本），已知这些染色体常参与各种起源肿瘤。由于12号染色体短臂缺失在ALL儿童中相对常见，我们还分析了12p上微卫星标记D12S308侧翼的一个区域。该区域包含一个遗传位点，其中含有假定的抑癌基因KIP1。
在分析的41例病例中的4例（9.7%）可记录到不同染色体上一个或两个位点的MI模式。3例为普通ALL，1例为T-ALL。1例显示两个同时存在的不稳定位点，1例通过同时使用微卫星标记D2S123和D18S58显示出另外两条带。
这些结果表明微卫星重复序列的基因不稳定在一部分儿童ALL中出现。遗传性和散发性实体瘤中记录到的错配修复错误可能因此参与血液系统恶性肿瘤。虽然在这些病例中基因组不稳定模式似乎表明存在突变表型和白血病转化的潜在易感性，但在具有明显非突变表型的病例中，需要深入研究靠近已知在ALL中发生的细胞遗传学和分子改变的其他基因组位点。
