Background. The 5-year overall survival (OS) rates of T-cell lymphocytic leukemia (T-ALL) are better for children (>90%) compared to adults (~57%). The early T-cell precursor (ETP) T-ALL subtype is prognostically unfavorable in adults, but less significant in pediatric T-ALL, and the diagnosis and prognosis of “near”-ETP is controversial. We compared protein and RNA expression patterns in pediatric and adult T-ALL to identify prognostic subgroups, and to further characterize ETP and near-ETP T-ALL in both age groups. Methods. Protein expression was assessed using RPPA methodology for 321 target proteins in 361 T-ALL patient samples from 292 pediatrics and 69 adults, including 103 ETP-ALL. RNA-sequencing was performed on 81 pediatric T-ALL samples. Results. We identified recurrent protein expression patterns that classified patients into ten protein expression signatures using the “MetaGalaxy” analysis. In adults, Cox regression analysis identified two risk-groups associated with OS (p= 0.0002) and complete remission duration (p< 0.001). Cluster analysis of adults and pediatric-ETP patients identified three ETP-clusters strongly associated with age. Pediatric ETP-patients with a pediatric-dominant expression profile were associated with a shorter OS (p= 0.04) and event-free survival (p= 0.05) compared to pediatric ETP-patients with an ETP expression profile that was also identified in adults. Conclusion. Our study demonstrates that proteomics are predictive of outcome in adult T-ALL and that we can identify a small subset of pediatric ETP with an inferior outcome. The observation that there are age-specific patterns supports the idea that the origin of T-ALL in most pediatric and adult patients is different, while overlapping patterns suggests that there are some with a common pathophysiology. Proteomics could enhance risk stratification in both pediatric and adults with T-ALL.
背景：相较于成人（约57%），儿童T细胞淋巴细胞白血病（T-ALL）的5年总生存率（OS）更高（>90%）。早期T细胞前体（ETP）T-ALL亚型在成人中预后较差，但在儿童T-ALL中预后意义较小，且“近”ETP亚型的诊断和预后存在争议。本研究通过比较儿童与成人T-ALL的蛋白质及RNA表达模式，旨在识别预后亚群，并进一步明确两个年龄组中ETP及近ETP T-ALL的特征。方法：采用反相蛋白微阵列技术对361例T-ALL患者样本（包括292例儿童和69例成人，其中103例为ETP-ALL）的321种靶蛋白表达进行评估。对81例儿童T-ALL样本进行RNA测序分析。结果：通过“MetaGalaxy”分析，我们识别出可重复的蛋白质表达模式，将患者分为十种蛋白质表达特征。在成人患者中，Cox回归分析确定了与OS（p=0.0002）及完全缓解持续时间（p<0.001）相关的两个风险组。对成人及儿童ETP患者的聚类分析识别出三个与年龄密切相关的ETP聚类。与具有成人中也存在的ETP表达特征的儿童ETP患者相比，呈现儿童主导表达特征的儿童ETP患者总生存期（p=0.04）和无事件生存期（p=0.05）更短。结论：本研究证明蛋白质组学可预测成人T-ALL的预后，并能识别出一小部分预后较差的儿童ETP亚群。年龄特异性表达模式的存在支持了大多数儿童与成人T-ALL起源不同的观点，而重叠的表达模式则提示部分患者存在共同的病理生理机制。蛋白质组学可增强儿童及成人T-ALL患者的风险分层能力。
肿瘤(癌症)患者之家