Genomic profiling of circulating tumor DNA for childhood cancers

IF 12.8 1区 医学 Q1 HEMATOLOGY
Shaohua Lei, Sujuan Jia, Sunitha Takalkar, Ti-Cheng Chang, Xiaotu Ma, Karol Szlachta, Ke Xu, Zhongshan Cheng, Yawei Hui, Selene C. Koo, Paul E. Mead, Qingsong Gao, Priyadarshini Kumar, Colin P. Bailey, Jobin Sunny, Alberto S. Pappo, Sara M. Federico, Giles W. Robinson, Amar Gajjar, Jeffrey E. Rubnitz, Sima Jeha, Ching-Hon Pui, Hiroto Inaba, Gang Wu, Jeffery M. Klco, Ruth G. Tatevossian, Charles G. Mullighan
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Abstract

The utility of circulating tumor DNA (ctDNA) analysis has not been well-established for disease detection and monitoring of childhood cancers, especially leukemias. We developed PeCan-Seq, a deep sequencing method targeting diverse somatic genomic variants in cell-free samples in childhood cancer. Plasma samples were collected at diagnosis from 233 children with hematologic, solid and brain tumors. All children with hematologic malignancy (n = 177) had detectable ctDNA at diagnosis. The median ctDNA fraction was 0.77, and 97% of 789 expected tumor variants were identified, including sequence mutations, copy number variations, and structural variations responsible for oncogenic fusions. In contrast, ctDNA was detected in 19 of 38 solid tumor patients and 1 of 18 brain tumor patients. Somatic variants from ctDNA were correlated with minimal residual disease levels as determined by flow cytometry in serial plasma samples from patients with B-cell acute lymphoblastic leukemia (B-ALL). We showcase multi-tumor detection by ctDNA analysis for a patient with concurrent B-ALL and neuroblastoma. In conclusion, PeCan-seq sensitively identified heterogeneous ctDNA alterations from 1 mL plasma for childhood hematologic malignancies and a subset of solid tumors. PeCan-seq provides a robust, non-invasive approach to augment comprehensive genomic profiling at diagnosis and mutation-specific detection during disease monitoring.

Abstract Image

针对儿童癌症的循环肿瘤 DNA 基因组特征分析
循环肿瘤 DNA(ctDNA)分析在儿童癌症(尤其是白血病)的疾病检测和监测方面的作用尚未得到充分证实。我们开发了 PeCan-Seq,这是一种针对儿童癌症无细胞样本中各种体细胞基因组变异的深度测序方法。我们在确诊时收集了 233 名血液肿瘤、实体瘤和脑瘤患儿的血浆样本。所有血液系统恶性肿瘤患儿(n = 177)在确诊时都检测到了ctDNA。ctDNA的中位数为0.77,在789种预期的肿瘤变异中,97%被鉴定出来,包括序列突变、拷贝数变异和导致致癌融合的结构变异。相比之下,38 名实体瘤患者中有 19 人检测到 ctDNA,18 名脑瘤患者中有 1 人检测到 ctDNA。在 B 细胞急性淋巴细胞白血病(B-ALL)患者的连续血浆样本中,ctDNA 的体细胞变异与流式细胞术测定的最小残留病水平相关。我们展示了通过ctDNA分析对一名同时患有B-ALL和神经母细胞瘤的患者进行多瘤检测的结果。总之,PeCan-seq 从 1 毫升血浆中灵敏地鉴定出了儿童血液恶性肿瘤和实体瘤亚群的异质性 ctDNA 改变。PeCan-seq 提供了一种稳健、无创的方法,可在诊断和疾病监测期间增强全面的基因组剖析和突变特异性检测。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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