Danilenko Marina, Clifford Steven C, Schwalbe Edward C
Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, UK.
Pharmacol Ther. 2021 Dec;228:107828. doi: 10.1016/j.pharmthera.2021.107828. Epub 2021 Mar 1.
Medulloblastoma is the most common malignant CNS tumor of childhood, affecting ~350 patients/year in the USA. In 2020, most children are cured of their disease, however, survivors are left with life-long late-effects as a consequence of intensive surgery, and application of chemo- and radio-therapy to the developing brain. A major contributor to improvements in patient survival has been the development of risk-stratified treatments derived from a better understanding of the prognostic value of disease biomarkers. The characterization and validation of these biomarkers has engendered a comprehensive understanding of the extensive heterogeneity that exists within the disease, which can occur both between and within tumors (inter- and intra-tumoral heterogeneity, respectively). In this review, we discuss inter-tumoral heterogeneity, describing the early characterization of clinical and histopathological disease heterogeneity, the more recent elucidation of molecular disease subgroups, and the potential for novel therapies based on specific molecular defects. We reflect on the limitations of current approaches when applied to a rare disease. We then review early investigations of intra-tumoral heterogeneity using FISH and immunohistochemical approaches, and focus on the application of next generation sequencing on bulk tumors to elucidate intra-tumoral heterogeneity. Finally, we critically appraise the applications of single-cell sequencing approaches and discuss their potential to drive next biological insights, and for routine clinical application.
髓母细胞瘤是儿童期最常见的中枢神经系统恶性肿瘤，在美国每年影响约350名患者。2020年，大多数儿童的疾病得到治愈，然而，由于进行了强化手术以及对发育中的大脑应用了化疗和放疗，幸存者会留下终身的晚期效应。患者生存率提高的一个主要因素是基于对疾病生物标志物预后价值的更好理解而开发的风险分层治疗方法。这些生物标志物的表征和验证使人们对该疾病中存在的广泛异质性有了全面的了解，这种异质性可分别在肿瘤之间和肿瘤内部发生（分别为肿瘤间和肿瘤内异质性）。在本综述中，我们讨论肿瘤间异质性，描述临床和组织病理学疾病异质性的早期特征、分子疾病亚组的最新阐明以及基于特定分子缺陷的新型疗法的潜力。我们思考当前方法应用于罕见疾病时的局限性。然后，我们回顾使用荧光原位杂交（FISH）和免疫组化方法对肿瘤内异质性的早期研究，并重点关注对整块肿瘤应用二代测序以阐明肿瘤内异质性。最后，我们批判性地评估单细胞测序方法的应用，并讨论其推动下一轮生物学见解以及用于常规临床应用的潜力。
