Germline Genetic Risk Stratification in ALL? GATA Get More Information.
Germline Genetic Risk Stratification in ALL? GATA Get More Information.
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ALL 的种系遗传风险分层？
DOI：
10.1093/jnci/djaa139
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Turcotte,LucieM
中科院分区：
文献类型：
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作者：
Spector,LoganG;Turcotte,LucieM
在过去的几十年里，小儿急性淋巴细胞白血病（ALL）的预后有了显著改善(1)，但在某些亚群疾病中仍有10%-20%的患者复发（2,3）。复发性疾病很难治疗，即使在现代，死亡率也接近50%。因此，预测复发已成为根据风险对患者进行分层并可能修改治疗的重要目标。长期确定的复发危险因素包括诊断时的年龄、诊断时的白细胞计数和DNA指数。最近，通过流式细胞术或聚合酶链反应在诱导结束时评估的最小残留病（MRD）已成为复发的有力预测指标。对此，Zhang等人(4)的研究增加了宿主种系遗传学，在一项针对高危儿童B-ALL患者的大型全基因组关联研究（GWAS）中，该研究预测了对诱导的次优反应（即高MRD）和独立于大多数基线危险因素的复发。该研究的特点是高质量的数据，包括3000多名儿童肿瘤组试验患者，通过标准化流式细胞术评估MRD，并通过参与部位的一致标准确定复发。采用适当的GWAS统计方法，将MRD解释为二分类或顺序变量。令人放心的是，出现的最高变异rs3824662在以MRD和复发为结果的多变量分析中仍然具有统计学意义，尽管如下所述，在调整细胞遗传亚型的分析中，统计相关性消失。除了统计上的证据外，有强有力的先验证据支持rs3824662的功能。该变异位于GATA3基因中，该基因编码一种影响淋巴生成的转录因子(5)。也许更重要的是，作者之前已经将这种变异与早期GWAS中BALL的发展联系起来，特别是ph样ALL(6)。这种关联的强度尤其显著，每个等位基因的优势比为3.85（95%置信区间= 2.71 ~ 5.47）。考虑到在控制ph样ALL时rs3824662与MRD的关联减弱，作者推测一些
Over the past several decades, outcomes for pediatric acute lymphoblastic leukemia (ALL) have improved dramatically (1), yet 10%-20% of patients still relapse in some subsets of disease (2, 3). Relapsed disease is difficult to treat, and mortality reaches nearly 50% even in the modern era. Thus, predicting relapse has become an important goal to stratify patients by risk and potentially to modify therapy. Long-established risk factors for relapse include age at diagnosis, white blood cell count at diagnosis, and DNA index. More recently, minimal residual disease (MRD) assessed by flow cytometry or polymerase chain reaction at the end of induction has emerged as a strong predictor of relapse. To this, the current study by Zhang et al.(4) adds host germline genetics, which predicted suboptimal response to induction (ie, high MRD) and relapse independently of most baseline risk factors in a large genome-wide association study (GWAS) of high-risk pediatric B-ALL patients. The study featured high-quality data, having consisted of more than 3000 patients on Children’s Oncology Group trials with MRD assessed by standardized flow cytometry and relapse determined by consistent criteria across participating sites. Appropriate statistical methods for GWAS were applied, with MRD construed as either a dichotomous or ordinal variable. Reassuringly, the top variant to appear, rs3824662, remained statistically significant in multivariable analyses with both MRD and relapse as the outcomes, although, as discussed below, in the analysis adjusting for cytogenetic subtypes the statistical association dissipated.Aside from the statistical evidence, there is strong prior evidence supporting the function of rs3824662. The variant is located in the GATA3 gene, which encodes a transcription factor that influences lymphopoiesis (5). Perhaps more important, the authors have previously linked the variant to development of BALL, particularly Ph-like ALL, in an earlier GWAS (6). This association was particularly notable for its strength, with an odds ratio of 3.85 per allele (95% confidence interval= 2.71 to 5.47). Given the diminishing association of rs3824662 with MRD when controlling for Ph-like ALL, the authors speculated that some of