Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum.
Chromosomal Instability Characterizes Pediatric Medulloblastoma but Is Not Tolerated in the Developing Cerebellum.
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DOI：
10.3390/ijms23179852
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发表时间：
2022-08-30
影响因子：
5.6
通讯作者：
Bruggeman, Sophia W. M.
中科院分区：
文献类型：
--
作者：
Bockaj, Irena;Martini, Tosca E., I;Smit, Marlinde J.;Armandari, Inna;Bakker, Bjorn;Wardenaar, Rene;Meeuwsen-de Boer, Tiny G. J.;Bakker, Petra L.;Spierings, Diana C. J.;Hoving, Eelco W.;Guryev, Victor;Foijer, Floris;Bruggeman, Sophia W. M.
关键词：
髓母细胞瘤是一种小儿脑恶性肿瘤，由四个转录亚群组成。结构和数量非整倍体在所有亚组中都很常见，尽管它们在第3组和第4组髓母细胞瘤以及SHH髓母细胞瘤的一个亚型SHHα中特别严重。这表明染色体不稳定性（CIN），导致非整倍体的过程，是髓母细胞瘤病理生理学的重要参与者。然而，目前尚不清楚髓母细胞瘤中是否存在持续的CIN，或者CIN是否影响发育中的小脑并促进肿瘤形成。为了研究这一点，我们对单个髓母细胞瘤细胞进行了核型分析，并证明了存在不同的肿瘤细胞克隆，这些克隆具有独特的拷贝数改变，这提示正在进行的CIN。我们还发现，在SHH髓母细胞瘤和假定的肿瘤细胞起源谱系的高度增殖区室中，与DNA复制、修复和有丝分裂相关的过程富集，后者也对遗传毒性应激敏感。然而，当挑战这些肿瘤细胞的起源与遗传病变诱导CIN使用转基因小鼠模型，我们没有发现大的染色体畸变小脑或髓母细胞瘤形成的证据。因此，我们得出结论，没有特定的基因突变的背景下，CIN是不能容忍的发展中的小脑在体内，因此，本身是不足以启动髓母细胞瘤。
Medulloblastoma is a pediatric brain malignancy that consists of four transcriptional subgroups. Structural and numerical aneuploidy are common in all subgroups, although they are particularly profound in Group 3 and Group 4 medulloblastoma and in a subtype of SHH medulloblastoma termed SHHα. This suggests that chromosomal instability (CIN), the process leading to aneuploidy, is an important player in medulloblastoma pathophysiology. However, it is not known if there is ongoing CIN in medulloblastoma or if CIN affects the developing cerebellum and promotes tumor formation. To investigate this, we performed karyotyping of single medulloblastoma cells and demonstrated the presence of distinct tumor cell clones harboring unique copy number alterations, which is suggestive of ongoing CIN. We also found enrichment for processes related to DNA replication, repair, and mitosis in both SHH medulloblastoma and in the highly proliferative compartment of the presumed tumor cell lineage-of-origin, the latter also being sensitive to genotoxic stress. However, when challenging these tumor cells-of-origin with genetic lesions inducing CIN using transgenic mouse modeling, we found no evidence for large chromosomal aberrations in the cerebellum or for medulloblastoma formation. We therefore conclude that without a background of specific genetic mutations, CIN is not tolerated in the developing cerebellum in vivo and, thus, by itself is not sufficient to initiate medulloblastoma.
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