DNA methylation-based profiling for paediatric CNS tumour diagnosis and treatment: a population-based study.

The Lancet. Child & adolescent health Pub Date : 2020-02-01 Epub Date: 2019-11-27 DOI:10.1016/S2352-4642(19)30342-6
Jessica C Pickles, Amy R Fairchild, Thomas J Stone, Lorelle Brownlee, Ashirwad Merve, Shireena A Yasin, Aimee Avery, Saira W Ahmed, Olumide Ogunbiyi, Jamie Gonzalez Zapata, Abigail F Peary, Marie Edwards, Lisa Wilkhu, Carryl Dryden, Dariusz Ladon, Mark Kristiansen, Catherine Rowe, Kathreena M Kurian, James A R Nicoll, Clare Mitchell, Tabitha Bloom, David A Hilton, Safa Al-Sarraj, Lawrence Doey, Paul N Johns, Leslie R Bridges, Aruna Chakrabarty, Azzam Ismail, Nitika Rathi, Khaja Syed, G Alistair Lammie, Clara Limback-Stanic, Colin Smith, Antonia Torgersen, Frances Rae, Rebecca M Hill, Steven C Clifford, Yura Grabovska, Daniel Williamson, Matthew Clarke, Chris Jones, David Capper, Martin Sill, Andreas von Deimling, Stefan M Pfister, David T W Jones, Darren Hargrave, Jane Chalker, Thomas S Jacques
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引用次数: 0

Abstract

Background: Marked variation exists in the use of genomic data in tumour diagnosis, and optimal integration with conventional diagnostic technology remains uncertain despite several studies reporting improved diagnostic accuracy, selection for targeted treatments, and stratification for trials. Our aim was to assess the added value of molecular profiling in routine clinical practice and the impact on conventional and experimental treatments.

Methods: This population-based study assessed the diagnostic and clinical use of DNA methylation-based profiling in childhood CNS tumours using two large national cohorts in the UK. In the diagnostic cohort-which included routinely diagnosed CNS tumours between Sept 1, 2016, and Sept 1, 2018-we assessed how the methylation profile altered or refined diagnosis in routine clinical practice and estimated how this would affect standard patient management. For the archival cohort of diagnostically difficult cases, we established how many cases could be solved using modern standard pathology, how many could only be solved using the methylation profile, and how many remained unsolvable.

Findings: Of 484 patients younger than 20 years with CNS tumours, 306 had DNA methylation arrays requested by the neuropathologist and were included in the diagnostic cohort. Molecular profiling added a unique contribution to clinical diagnosis in 107 (35%; 95% CI 30-40) of 306 cases in routine diagnostic practice-providing additional molecular subtyping data in 99 cases, amended the final diagnosis in five cases, and making potentially significant predictions in three cases. We estimated that it could change conventional management in 11 (4%; 95% CI 2-6) of 306 patients. Among 195 historically difficult-to-diagnose tumours in the archival cohort, 99 (51%) could be diagnosed using standard methods, with the addition of methylation profiling solving a further 34 (17%) cases. The remaining 62 (32%) cases were unresolved despite specialist pathology and methylation profiling.

Interpretation: Together, these data provide estimates of the impact that could be expected from routine implementation of genomic profiling into clinical practice, and indicate limitations where additional techniques will be required. We conclude that DNA methylation arrays are a useful diagnostic adjunct for childhood CNS tumours.

Funding: The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK, and the National Institute of Health Research.

基于DNA甲基化的儿童中枢神经系统肿瘤诊断和治疗分析:一项基于人群的研究。
背景:在肿瘤诊断中使用基因组数据存在显著差异,尽管有几项研究报告提高了诊断准确性、选择靶向治疗和试验分层,但与传统诊断技术的最佳整合仍不确定。我们的目的是评估分子谱分析在常规临床实践中的附加价值以及对常规和实验治疗的影响。方法:这项基于人群的研究评估了DNA甲基化分析在儿童中枢神经系统肿瘤中的诊断和临床应用,使用了英国的两个大型国家队列。在诊断队列中,包括2016年9月1日至2018年9月1日期间常规诊断的中枢神经系统肿瘤,我们评估了甲基化谱如何改变或改进常规临床实践中的诊断,并估计了这将如何影响标准患者管理。对于诊断困难病例的档案队列,我们确定了有多少病例可以使用现代标准病理学解决,有多少只能使用甲基化谱解决,有多少仍然无法解决。研究结果:在484例年龄小于20岁的中枢神经系统肿瘤患者中,306例患者接受了神经病理学家要求的DNA甲基化测序,并被纳入诊断队列。分子谱分析对107例(35%;在306例常规诊断实践中,95% CI为30-40,其中99例提供了额外的分子分型数据,5例修改了最终诊断,3例做出了潜在的重要预测。我们估计它可以在11 (4%;306例患者的95% CI为2-6。在档案队列中195例历史上难以诊断的肿瘤中,99例(51%)可以使用标准方法诊断,加上甲基化分析,另外34例(17%)可以解决。其余62例(32%)尽管有专家病理和甲基化分析,但仍未得到解决。综上所述,这些数据提供了基因组分析在临床实践中常规实施可能产生的影响的估计,并指出了需要额外技术的局限性。我们得出结论,DNA甲基化阵列是儿童中枢神经系统肿瘤的有用诊断辅助手段。资助:脑肿瘤慈善机构、英国儿童癌症、大奥蒙德街医院儿童慈善机构、奥利维亚·霍德森癌症基金、英国癌症研究中心和国家卫生研究所。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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