Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Pediatric Glioma Research Group, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nat Rev Cancer. 2019 Aug;19(8):420-438. doi: 10.1038/s41568-019-0169-x. Epub 2019 Jul 12.
The spectrum of tumours arising in childhood is fundamentally different from that seen in adults, and they are known to be divergent from adult malignancies in terms of cellular origins, epidemiology, genetic complexity, driver mutations and underlying mutational processes. Despite the immense knowledge generated through sequencing efforts and functional characterization of identified (epi-)genetic alterations over the past decade, the clinical implications of this knowledge have so far been limited. Novel preclinical platforms such as the European Innovative Therapies for Children with Cancer-Paediatric Preclinical Proof-of-Concept Platform and the US-based Pediatric Preclinical Testing Consortium are being developed to try to change this by aiming to recapitulate the extensive heterogeneity of paediatric tumours and thereby, hopefully, improve the ability to predict clinical benefit. Numerous studies have also been established worldwide to provide patients with access to real-time molecular profiling and the possibility of more precise mechanism-of-action-based treatments. In addition to tumour-intrinsic findings and mechanisms, ongoing studies are investigating features such as the immune microenvironment of paediatric tumours in comparison with adult cancers - currently of very timely clinical relevance. However, there is an ongoing need for rigorous preclinical biomarker and target validation to feed into the next generation of molecularly stratified clinical trials. This Review aims to provide a comprehensive state-of-the-art overview of the molecular landscape of paediatric solid tumours, including their underlying genomic alterations and interactions with the microenvironment, complemented with our current understanding of potential therapeutic vulnerabilities and how these can be preclinically tested using more accurate predictive methods. Finally, we provide an outlook on the challenges and opportunities associated with translating this overwhelming scientific progress into real clinical benefit.
儿童期发生的肿瘤谱与成人完全不同，并且已知在细胞起源、流行病学、遗传复杂性、驱动突变和潜在突变过程方面与成人恶性肿瘤不同。尽管在过去十年中通过测序工作和对已确定（表观）遗传改变的功能特征分析已经产生了巨大的知识，但迄今为止，这些知识的临床意义还很有限。新型的临床前平台，如欧洲儿童癌症创新治疗方法-儿科临床前概念验证平台和美国儿科临床前测试联盟，正在开发中，旨在通过旨在再现儿科肿瘤的广泛异质性来试图改变这种情况，从而有望提高预测临床获益的能力。全世界还开展了许多研究，为患者提供实时分子分析的机会，并有可能进行更精确的基于作用机制的治疗。除了肿瘤内在的发现和机制外，正在进行的研究还在研究儿科肿瘤的免疫微环境等特征，与成人癌症相比，目前具有非常及时的临床相关性。然而，仍需要严格的临床前生物标志物和靶标验证，以促进下一代分子分层临床试验的发展。本综述旨在全面概述儿科实体瘤的分子图谱，包括其潜在的基因组改变及其与微环境的相互作用，同时我们还了解了潜在的治疗弱点以及如何使用更准确的预测方法在临床前进行测试。最后，我们展望了将这种压倒性的科学进展转化为实际临床获益所面临的挑战和机遇。
