Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma,British Journal of Cancer

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Whole-genome sequencing facilitates patient-specific quantitative PCR-based minimal residual disease monitoring in acute lymphoblastic leukaemia, neuroblastoma and Ewing sarcoma
British Journal of Cancer ( IF 8.8 ) Pub Date : 2021-09-01 , DOI: 10.1038/s41416-021-01538-z
Vinod Vijay Subhash _{1,

2} , Libby Huang ₁ , Alvin Kamili _{1,

2} , Marie Wong _{1,

2} , Dan Chen ₁ , Nicola C Venn ₁ , Caroline Atkinson _{1,

2} , Chelsea Mayoh _{1,

2} , Pooja Venkat ₁ , Vanessa Tyrrell _{1,

2} , Glenn M Marshall _{1,

2,

3} , Mark J Cowley _{1,

2} , Paul G Ekert _{1,

2,

4,

5} , Murray D Norris _{1,

6} , Michelle Haber _{1,

2} , Michelle J Henderson _{1,

2} , Rosemary Sutton _{1,

2} , Jamie I Fletcher _{1,

2} , Toby N Trahair _{1,

2,

3}

Affiliation

Background

Minimal residual disease (MRD) measurement is a cornerstone of contemporary acute lymphoblastic leukaemia (ALL) treatment. The presence of immunoglobulin (Ig) and T cell receptor (TCR) gene recombinations in leukaemic clones allows widespread use of patient-specific, DNA-based MRD assays. In contrast, paediatric solid tumour MRD remains experimental and has focussed on generic assays targeting tumour-specific messenger RNA, methylated DNA or microRNA.

Methods

We examined the feasibility of using whole-genome sequencing (WGS) data to design tumour-specific polymerase chain reaction (PCR)-based MRD tests (WGS-MRD) in 18 children with high-risk relapsed cancer, including ALL, high-risk neuroblastoma (HR-NB) and Ewing sarcoma (EWS) (n = 6 each).

Results

Sensitive WGS-MRD assays were generated for each patient and allowed quantitation of 1 tumour cell per 10⁻⁴ (0.01%)–10^–5 (0.001%) mononuclear cells. In ALL, WGS-MRD and Ig/TCR-MRD were highly concordant. WGS-MRD assays also showed good concordance between quantitative PCR and droplet digital PCR formats. In serial clinical samples, WGS-MRD correlated with disease course. In solid tumours, WGS-MRD assays were more sensitive than RNA-MRD assays.

Conclusions

WGS facilitated the development of patient-specific MRD tests in ALL, HR-NB and EWS with potential clinical utility in monitoring treatment response. WGS data could be used to design patient-specific MRD assays in a broad range of tumours.

中文翻译：

全基因组测序有助于在急性淋巴细胞白血病、神经母细胞瘤和尤文肉瘤中进行基于患者特异性定量 PCR 的微小残留病监测

背景

微小残留病 (MRD) 测量是当代急性淋巴细胞白血病 (ALL) 治疗的基石。白血病克隆中免疫球蛋白 (Ig) 和 T 细胞受体 (TCR) 基因重组的存在允许广泛使用患者特异性、基于 DNA 的 MRD 检测。相比之下，儿科实体瘤 MRD 仍处于实验阶段，并专注于针对肿瘤特异性信使 RNA、甲基化 DNA 或 microRNA 的通用检测。

方法

我们研究了使用全基因组测序 (WGS) 数据设计基于肿瘤特异性聚合酶链反应 (PCR) 的 MRD 测试 (WGS-MRD) 的可行性，用于 18 名患有高危复发性癌症的儿童，包括 ALL、高危神经母细胞瘤 (HR-NB) 和尤文肉瘤 (EWS)（每个n = 6）。

结果

为每位患者生成灵敏的 WGS-MRD 测定，并允许对每 10 ^-4 (0.01%)–10 ^-5 (0.001%) 个单核细胞中 1 个肿瘤细胞进行定量。在 ALL 中，WGS-MRD 和 Ig/TCR-MRD 高度一致。WGS-MRD 分析还显示定量 PCR 和液滴数字 PCR 格式之间的良好一致性。在系列临床样本中，WGS-MRD 与病程相关。在实体瘤中，WGS-MRD 检测比 RNA-MRD 检测更敏感。