JCO：鉴定出9个促进白血病产生的基因突变

来自英国纽卡斯尔大学的研究人员发现三种关键性的遗传错误：它们能够决定成年病人如何患上白血病和对治疗方法作出反应，可能有助于医生们改进未来的治疗方法。2012年7月30日，这项突破性研究发表在Journal of Clinical Oncology期刊上。

急性淋巴细胞白血病(acute lymphoblastic leukaemia, ALL)是一种血癌，特征在于白细胞发生基因突变而不受控制地增殖而将健康的血细胞挤出去。在这项研究中，研究人员研究了450名被诊断患有ALL的青年人和成年人体内白血病细胞中9个新发现的遗传突变。

他们证实这些新突变的发生率比期望中更高，而且还发现三分之二以上的病人携带至少一个突变。再者，他们还发现这些新突变中的三个是“高风险”的标记物，携带这三种突变中之一的病人当接受标准疗法时有更加高的风险发生白血病复发或死亡。超过四分之一的病人携带这些高风险突变中的一个或多个，这种突变发生率明显高于ALL儿童中观察到的相应突变发生率。

论文第一作者Anthony Moorman教授说，“这项研究代表着我们在理解成年人ALL遗传突变的临床重要性上取得一次重要性的进展。”

本文编译自Scientists identify genetic drivers of leukaemia

doi: 10.1200/JCO.2011.40.3907
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IGH@ Translocations, CRLF2 Deregulation, and Microdeletions in Adolescents and Adults With Acute Lymphoblastic Leukemia

Anthony V. Moorman⇓, Claire Schwab, Hannah M. Ensor, Lisa J. Russell, Heather Morrison, Lisa Jones, Dino Masic, Bella Patel, Jacob M. Rowe, Martin Tallman, Anthony H. Goldstone, Adele K. Fielding and Christine J. Harrison

Purpose To determine the prevalence and prognostic impact of significant acute lymphoblastic leukemia (ALL) –related genes: CRLF2 deregulation (CRLF2-d), IGH@ translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, and EBF1 in adolescents and adults. Patients and Methods The cohort comprised 454 patients (age 15 to 60 years old) treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used to detect these genetic alterations. Results Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n = 13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There was little overlap between IGH@-t, CRLF2-d, and established chromosomal abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5-year event-free survival, relapse-free survival (RFS), and overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%, respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated with an inferior outcome in univariate but not multivariate analysis. In particular, CRLF2-d patients had a lower RFS compared with other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%, respectively). Conclusion CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.