Brassesco María S, Montaldi Ana P, Gras Diana E, Camparoto Marjori L, Martinez-Rossi Nilce M, Scrideli Carlos A, Tone Luiz G, Sakamoto-Hojo Elza T
Departamento de Genética, Faculdade de Medicina de Ribeirão Preto-USP, Universidade de São Paulo, São Paulo, Brazil.
Mutagenesis. 2009 Mar;24(2):153-60. doi: 10.1093/mutage/gen063. Epub 2008 Nov 21.
The successful treatment of paediatric malignancies by multimodal therapy has improved outcomes for children with cancer, especially those with acute lymphoblastic leukaemia (ALL). Second malignant neoplasms, however, represent a serious complication after treatment. Depending on dosage, 2-12% of patients treated with topoisomerase II inhibitors and/or alkylating agents develop treatment-related acute myeloid leukaemia characterized by translocations at 11q23. Our goal was to study MLL rearrangements in peripheral lymphocytes using cytogenetic and molecular methods in order to evaluate the late effects of cancer therapy in patients previously treated for childhood ALL. Chromosomal rearrangements at 11q23 were analysed in cytogenetic preparations from 49 long-term ALL survivors and 49 control individuals. Patients were subdivided depending on the inclusion or omission of topoisomerase II inhibitors (VP-16 and/or VM-26) in their treatment protocol. The statistical analysis showed significant (P = 0.007) differences between the frequency of translocations observed for the groups of patients and controls. These differences were also significant (P = 0.006) when the groups of patients (independent of the inclusion of topoisomerase II inhibitors) and controls were compared (P = 0.006). The frequencies of extra signals, however, did not differ between groups of patients and controls. Several MLL translocations were detected and identified by inverse polymerase chain reaction, followed by cloning and sequencing. Thirty-five patients (81%) presented putative translocations; among those, 91% corresponded with t(4;11) (q21;q23), while the other 9% corresponded with t(11;X), t(8;11)(q23;q23) and t(11;16). Our results indicate an increase in MLL aberrations in childhood ALL survivors years after completion of therapy. The higher frequency in this cohort might be associated with therapy using anti-tumoural drugs, independent of the inclusion of topoisomerase II inhibitors. Even though the biological significance of these rearrangements needs further investigation, they demonstrate a degree of genome instability, indicating the relevance of cytogenetic and molecular studies during the follow-up of patients in complete clinical remission.
多模式疗法成功治疗儿童恶性肿瘤改善了癌症患儿的治疗效果，尤其是急性淋巴细胞白血病（ALL）患儿。然而，第二原发性恶性肿瘤是治疗后的一种严重并发症。根据剂量不同，接受拓扑异构酶II抑制剂和/或烷化剂治疗的患者中有2% - 12%会发生与治疗相关的急性髓系白血病，其特征是11q23发生易位。我们的目标是使用细胞遗传学和分子方法研究外周血淋巴细胞中的MLL重排，以评估既往接受儿童ALL治疗的患者癌症治疗的晚期效应。对49名长期ALL幸存者和49名对照个体的细胞遗传学标本进行11q23染色体重排分析。根据治疗方案中是否包含拓扑异构酶II抑制剂（VP - 16和/或VM - 26）对患者进行分组。统计分析显示，患者组和对照组观察到的易位频率存在显著差异（P = 0.007）。当比较患者组（无论是否包含拓扑异构酶II抑制剂）和对照组时，这些差异也具有显著性（P = 0.006）。然而，额外信号的频率在患者组和对照组之间没有差异。通过反向聚合酶链反应检测并鉴定了几种MLL易位，随后进行克隆和测序。35名患者（81%）出现推定易位；其中，91%对应于t(4;11)(q21;q23)，而另外9%对应于t(11;X)、t(8;11)(q23;q23)和t(11;16)。我们的结果表明，在治疗完成多年后，儿童ALL幸存者中MLL畸变增加。该队列中较高的频率可能与使用抗肿瘤药物治疗有关，与是否包含拓扑异构酶II抑制剂无关。尽管这些重排的生物学意义需要进一步研究，但它们显示出一定程度的基因组不稳定性，表明在完全临床缓解的患者随访期间进行细胞遗传学和分子研究的相关性。
