A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
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DOI：
10.1016/s1470-2045(08)70339-5
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发表时间：
2009-02
期刊：
影响因子：
51.1
通讯作者：
Pieters, Rob
中科院分区：
文献类型：
--
作者：
Den Boer, Monique L.;van Slegtenhorst, Marjon;De Menezes, Renee X.;Cheok, Meyling H.;Buijs-Gladdines, Jessica G. C. A. M.;Peters, Susan T. C. J. M.;Van Zutven, Laura C. M.;Beverloo, H. Berna;Van der Spek, Peter J.;Escherich, Gaby;Horstmann, Martin A.;Janka-Schoub, Gritta E.;Kamps, Willem A.;Evans, William E.;Pieters, Rob
在儿童急性淋巴细胞白血病（ALL）中，遗传亚型确定了进一步治疗的风险群体。然而，25%的前体BALL目前基因未分类，预后中等。本研究使用全基因组策略来揭示新的生物学见解和推进儿童ALL的预后分类。采用双环交叉验证法构建基于190例新诊断儿科ALL细胞基因表达的分类器，然后在107例新诊断儿科ALL的独立队列中进行验证。利用分类基因探针集的层次聚类分析揭示了一种新的ALL亚型，其潜在的遗传异常通过比较基因组杂交阵列和分子细胞遗传学进行了表征。在发现队列中，分类器的预测准确率中位数为90%，在独立验证队列中为87.9%。在发现和验证队列中，目前基因未分类的病例中有很大一部分与bcr - abl阳性病例聚集在一起。这些bcr - abl样病例占ALL病例的15-20%，与其他前体B-ALL病例（84.4%,95%CI: 76.8%-92.1%； P=0.012）相比，预后非常不利（5年无病生存率59.5%,95%CI: 37.1%-81.9%），与bcr - abl阳性ALL的预后差（51.9%,95%CI: 23.1%-80.6%）相似，验证队列证实了这一点。进一步的遗传学研究显示，与其他ALL病例相比，bcr - abl样亚型的特征是与b细胞发育相关的基因缺失频率高（82%），包括IKAROS、E2A、EBF1、PAX5和VPREB1 （36%, p=0.0002）。与其他前体B-ALL病例相比，bcr - abl样白血病细胞对l -天冬酰胺酶的耐药中值为70倍（p=0.001），对柔红霉素的耐药中值为1.6倍（p=0.017），而强的松龙和长春新碱的毒性没有显著差异。通过基因表达谱进行分类，确定了当前诊断程序未检测到的一种新型ALL亚型，但它包含了最大的治疗失败高风险患者群体。需要新的治疗策略来改善这种新型高危亚型ALL的预后。荷兰癌症协会，索菲亚医学研究基金会，鹿特丹儿科肿瘤基金会，荷兰基因组学倡议/荷兰科学研究组织医疗系统生物学中心，美国国家卫生研究所，美国国家癌症研究所和美国黎巴嫩叙利亚联合慈善机构。
In childhood acute lymphoblastic leukemia (ALL) genetic subtypes are recognized that determine the risk-group for further treatment. However, 25% of precursor BALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. A classifier based on gene expression in ALL cells from 190 newly diagnosed pediatric cases was constructed using a double-loop cross-validation method and next, was validated on an independent cohort of 107 newly diagnosed pediatric ALL cases. Hierarchical cluster analysis using classifying gene probe sets then revealed a novel ALL subtype for which underlying genetic abnormalities were characterized by comparative genomic hybridization-arrays and molecular cytogenetics. The prediction accuracy of the classifier was median 90% in the discovery cohort and 87.9% in the independent validation cohort. A significant part of the currently genetically unclassified cases clustered with BCR-ABL-positive cases in both the discovery and validation cohort. These BCR-ABL-like cases represent 15–20% of ALL cases and have a highly unfavorable outcome (5-year disease-free survival 59.5%, 95%CI: 37.1%–81.9%) compared to other precursor B-ALL cases (84.4%, 95%CI: 76.8%–92.1%; P=0.012), similar to the poor prognosis of BCR-ABL-positive ALL (51.9%, 95%CI: 23.1%–80.6%), as was confirmed in the validation cohort. Further genetic studies revealed that the BCR-ABL-like subtype is characterized by a high frequency of deletions in genes involved in B-cell development (82%), including IKAROS, E2A, EBF1, PAX5 and VPREB1, compared to other ALL cases (36%, p=0.0002). BCR-ABL-like leukemic cells were median >70-times resistant to L-asparaginase (p=0.001) and 1.6-times more resistant to daunorubicin (p=0.017) compared to other precursor B-ALL cases whereas the toxicity of prednisolone and vincristine did not significantly differ. Classification by gene expression profiling identified a novel subtype of ALL not detected by current diagnostic procedures but which comprises the largest group of patients with a high-risk of treatment failure. New treatment strategies are needed to improve outcome for this novel high-risk subtype of ALL. Dutch Cancer Society, Sophia Foundation for Medical Research, Pediatric Oncology Foundation Rotterdam, Center of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute and American Lebanese Syrian Associated Charities.