PO.CL12.03 · 临床研究

基于云的计算框架用于儿童急性淋巴细胞白血病的个体化基因组分析：一项全国性多中心真实世界临床研究

Cloud-based computational framework for individualized genomic analysis in pediatric acute lymphoblastic leukemia: A nationwide multi-center real-world clinical study

编号 5283 展板 3 时间 4/21 09:00–12:00 区域 Section 44 主讲 Han Wang, PhD

分会场 Epigenetics, Cytogenetics, and Clinical Molecular Genetics

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作者与单位 Authors & Affiliations

Han Wang¹, Jiaoyang Cai¹, Jie Yu², Shaoyan Hu³, Yongjun Fang⁴, Ju Gao⁵, Jian Li⁶, Hua Jiang⁷, Xiuli Ju⁸, Sixi Liu⁹, Wenyong Kuang¹⁰, Runming Jin¹¹, Liangchun Yang¹², Xuedong Wu¹³, Xiaowen Zhai¹⁴, Qun Hu¹⁵, Hui Jiang¹⁶, Ningling Wang¹⁷, Chi Kong Li¹⁸, Lirong Sun¹⁹, Jiao Jin²⁰, Chun Li²¹, Changda Liang²², Yan Dai²³, Kaili Pan²⁴, Hao Xiong²⁵, Ching-Hon Pui²⁶, Shuhong Shen²⁷, Yu Liu¹

¹Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,²Chongqing Medical University Affiliated Children's Hospital, Chongqing, China,³Children's Hospital of Soochow Universit, Suzhou, China,⁴Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China,⁵West China Second University Hospital, Sichuan University, Chengdu, China,⁶Fujian Medical University Union Hospital, Fuzhou, China,⁷Guangzhou Women and Children's Medical Center, Guangzhou, China,⁸Qilu Hospital of Shandong University, Jinan, China,⁹Shenzhen Children’s Hospital, Shenzhen, China,¹⁰Hunan Children's Hospital, Changsha, China,¹¹Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,¹²Xiangya Hospital Central South University, Changsha, China,¹³Nanfang Hospital, Southern Medical University, Guangzhou, China,¹⁴Children's hospital of Fudan university, Shanghai, China,¹⁵Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,¹⁶Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,¹⁷Anhui Medical University Second Affiliated Hospital, Hefei, China,¹⁸Hong Kong Children’s Hospital, Hong Kong, Hong Kong,¹⁹Affiliated Hospital of Qingdao University, Qingdao, China,²⁰The Affiliated Hospital of Guizhou University, Guiyang, China,²¹Anhui Provincial Hosptical, Anhui, China,²²Jiangxi Provincial Children's Hospital, Nanchang, China,²³The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China,²⁴Xi 'an Northwest Women and Children Hospital, Xi 'an, China,²⁵Wuhan Children’s Hospital, Wuhan, China,²⁶Chair, Dept. of Oncology, St. Jude Children's Research Hospital, Memphis, TN,²⁷Department of Hematology & Oncology, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

摘要 Abstract

中文摘要

急性淋巴细胞白血病（ALL）是最常见的儿童癌症。虽然基因组研究已鉴定出ALL的关键分子亚型和异常，但在大型回顾性队列中，它需要整合多组学数据以完成复杂且耗时的分析。在真实世界中进行个体化临床基因组分析具有挑战性。我们呈现一项全国性精准基因组研究，作为中国儿童肿瘤协作组ALL 2020临床试验的一部分。2020年至2023年间，来自中国15个省份25个医疗中心的6486例儿童ALL患者被纳入。在诊断期间对5103例患者进行了RNA-seq。我们开发了国家儿童医学中心ALL生物云（NCMC-ABC），这是一个用于实时RNA-seq数据处理的自动化、基于云的框架。NCMC-ABC旨在从单一RNA-seq数据分析多种临床相关的基因组异常，包括分子亚型、编码和非编码驱动突变、融合和CNV。从样本采集到临床报告的中位周转时间在所有医院中为14天，与临床治疗时间线相一致。我们建立了儿童ALL的分子亚型分类框架，成功将94.94%的B-ALL分类为20个亚型，将86.38%的T-ALL分类为11个亚型。该框架显著改进了传统的MICM方法，后者仅对48.58%的B-ALL进行分类，且未涵盖T-ALL亚型。分类的增强得益于对关键融合（DUX4、PAX5、ZNF384、MEF2D重排）和突变（PAX5 P80R和IKZF1 N159Y）检测的改进。同时，我们实现了对HYPO、HYPER和KMT2A B-ALL的更精确分型。经过完善的亚型揭示了中国B-ALL患者的独特特征，与西方队列相比，HYPER、ETV6、DUX4和PH亚型的频率较高，而Ph样、iAMP21和HYPO的频率较低。重要的是，完善的框架直接改善了患者的风险分层。我们鉴定出每例患者中位2.44个致病性SNP/indel和1.28个融合。在B-ALL中于259个基因中检测到驱动突变，在T-ALL中于156个基因中检测到。与西方队列相比，我们的队列中观察到不同的驱动突变谱。RAS通路突变（NRAS、KRAS和PTPN11）在中国患者中更为常见，而JAK-STAT通路（JAK2、IL7R、SH2B3和CRLF2）在西方队列中更常发生突变。我们观察到这些异常的直接临床相关性。例如，携带TP53和NR3C1突变的患者显示出较差的治疗反应。 NCMC-ABC在全国性多中心儿童ALL临床试验中的实施证明了其在真实世界中的有效性和可行性，改善了临床中的风险分层和治疗决策。

查看英文原文 English abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While genomic studies have identified key molecular subtypes and aberrations in ALL, it requires integrating multi-omics data to complete complex and time-consuming analyses in large retrospective cohorts. It is challenging to perform individualized clinical genomic analysis in real-world. We present a nationwide precision genomic study as part of the Chinese Children Cancer Group ALL 2020 clinical trial. Between 2020 and 2023, 6486 pediatric ALL patients were enrolled from 25 medical centers across 15 provinces in China. RNA-seq was performed for 5103 patients during diagnosis. We developed the National Children's Medical Center ALL Bio-Cloud (NCMC-ABC), an automated, cloud-based framework for real-time RNA-seq data process. NCMC-ABC is designed to analyze multiple clinically relevant genomic aberrations from single RNA-seq data, including molecular subtypes, coding and noncoding driver mutations, fusions and CNVs. The median turnaround time from sample collection to clinical reporting was 14 days across all hospitals, aligning with clinical treatment timelines. We established a molecular subtype classification framework for pediatric ALL, and successfully classified 94.94% of B-ALLs into 20 subtypes and 86.38% of T-ALLs into 11 subtypes. This framework significantly improved the traditional MICM approach, which classified only 48.58% of B-ALLs and did not account for T-ALL subtypes. The enhanced classification is due to the improved detection of key fusions ( DUX4 , PAX5 , ZNF384 , MEF2D rearrangements) and mutations ( PAX5 P80R and IKZF1 N159Y). Meanwhile, we achieved more precise subtyping of HYPO, HYPER and KMT2A BALLs. The refined subtypes unveiled a distinct profile of Chinese B-ALL patients, with higher frequencies of HYPER , ETV6, DUX4 and PH subtypes, and lower frequencies of Ph-like, iAMP21 and HYPO, compared to Western cohorts. Importantly, the refined framework directly improved the risk stratification of patients. We identified a median of 2.44 pathogenic SNPs/indels and 1.28 fusions per patient. The driver mutations were detected in 259 genes in B-ALL and 156 in T-ALL. We observed different driver mutation profiles in our cohort compared to the Western cohort. Mutations in RAS pathway ( NRAS , KRAS and PTPN11 ) were more frequent in Chinese patients, whereas the JAK-STAT ( JAK2 , IL7R , SH2B3 and CRLF2 ) pathway was more frequently mutated in Western cohort. We observed direct clinical relevance of these aberrations. For example, patients with TP53 and NR3C1 mutations showed inferior treatment response. The implementation of NCMC-ABC in a nationwide multicenter pediatric ALL clinical trial demonstrated its effectiveness and feasibility in real-world, improving risk stratification and therapeutic decision making in clinic.

利益披露 Disclosure

H. Wang, None.. J. Cai, None.. J. Yu, None.. Y. Fang, None.. J. Gao, None.. J. Li, None.. H. Jiang, None.. X. Ju, None.. S. Liu, None.. W. Kuang, None.. R. Jin, None.. L. Yang, None.. X. Wu, None.. X. Zhai, None.. Q. Hu, None.. H. Jiang, None.. N. Wang, None.. C. Li, None.. L. Sun, None.. J. Jin, None.. C. Li, None.. C. Liang, None.. Y. Dai, None.. K. Pan, None.. H. Xiong, None.. S. Shen, None.. Y. Liu, None.

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