2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, Budapest, H-1094, Hungary.
MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, H-1117, Hungary.
J Hematol Oncol. 2019 Mar 15;12(1):29. doi: 10.1186/s13045-019-0712-y.
Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations.The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials.To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates.
儿童髓母细胞瘤（MB）具有异质性，可分为四个分子亚组。暂定的非无翅型激活（WNT）/非 sonic 刺猬激活（SHH）类别将第 3 组和第 4 组结合在一起，代表了所有 MB 的三分之二以上，同时具有最高的转移率和最不被理解的病理学。分子时代扩展了我们对 MB 肿瘤发生中涉及的分子异常的认识，在这里，我们回顾导致非 WNT/SHH MB 形成的过程。异质性第 3 组和第 4 组 MB 经常携带罕见的个体遗传改变，但新兴的特征表明，罕见的事件集中在共同的、潜在的可靶向信号通路。一个共同的主题是表观遗传调控的改变，靶向表观遗传机制的体外方法很有前途。越来越多的证据表明存在一个中间的、混合特征组，沿着第 3 组和第 4 组，未来的澄清对于一致的分类至关重要，因为错误识别患者样本对治疗和临床试验有严重影响。为了降低 MB 的高死亡率，我们需要识别疾病传播和复发的机制。目前的临床前模型不能代表第 3 组和第 4 组的全部异质性：所有现有的第 3 组细胞系都被 MYC 扩增，大多数小鼠模型类似于 MYC 激活的 MB。临床样本提供了关于原发肿瘤和转移克隆之间遗传差异的大量信息，但很少有复发性 MB 被切除。分子分层的治疗选择有限，靶向治疗仍处于临床前开发阶段。需要从多个前沿攻击这些侵袭性肿瘤，以提高停滞不前的生存率。
