Medulloblastoma: From TP53 Mutations to Molecular Classification and Liquid Biopsy

Abstract

A recent paradigm shift in the diagnostics of medulloblastoma allowed the distinction of four major groups defined by genetic data rather than histology. This new molecular classification correlates better with prognosis and will allow for the better clinical management of therapies targeting druggable mutations, but also offer a new combination of monitoring tumor development in real-time and treatment response by sequential liquid biopsy. This review highlights recent developments after a century of milestones in neurosurgery and radio- and chemotherapy, but also controversial theories on the cell of origin, animal models, and the use of liquid biopsy.

Keywords: TP53 mutation; animal models; diagnostics; liquid biopsy; medulloblastoma; molecular classification; precision oncology; transcriptome.

Figure 4

Liquid biopsy. A distance to the tumor in the brain body fluids can be taken at low risk to reveal genetic information from the tumor to guide clinical treatment. CSF—cerebrospinal fluid; CTC—circulating tumor cell; EV—extracellular vesicle. Adapted with permission from [24,46]. Created/modified with SMART [63], licensed by a Creative Commons Attribution 3.0 Unported License [64].

Figure 5

Biomarker during tumor development. Close monitoring of ctDNA allows for the diagnosis as well as early detection of minimal residual disease (MRD) to guide treatment. Adapted with permission from [24,46].

Figure 1

The rat tumor model of PNETs is histologically indistinguishable from human medulloblastoma. Histology of tumors induced in CNS transplants by retroviral gene expression of SV40 large T antigen. (A) HE-stain with typical histology, incl. neuroblastic Homer-Wright rosettes as a sign of an early stage neuronal differentiation. (B) SYNAPTOPHYSIN expression: immunohistochemical staining with polyclonal antibodies shows a strong synaptophysin expression, indicating neuronal differentiation, (C) GFAP expression: astrocytic differentiation of a tumor cell cluster. (D) Massive infiltration of tumor cells into the hippocampus of the adjacent host brain. Immunohistochemical staining for synaptophysin. (E) Immunohistochemical detection of SV40 large T antigen in the tumor tissue. The monoclonal antibody Pab108 to large T is used for the reaction. Note the characteristic nuclear staining pattern and the absence of immunoreactivity in capillary endothelial cells. (F) Secondary transplant obtained after intracerebral injection of a tumor-derived cell line. The typical morphology is completely preserved. (reproduced/adapted from Eibl et al., 1994 [14]).

Figure 2

Cell line derived from a SV40 LT-induced PNET. A characteristic property is the formation of cell clusters with long cell processes and other cytological features of primary neuronal cells.

Figure 3

Autoradiography from 1991 of the first detected TP53 mutations in primary medulloblastoma tissue. Extracted DNA from frozen tumor samples was analyzed by the SSCP-PCR of exon 6 of the TP53 gene incorporating radioactively labelled dCTP. Despite the identical length, conformational changes as a result of point mutations in the sequence compared to wild-type DNA can be revealed on an acrylamide gel when run as single-stranded (denatured) DNA fragments. Of five medulloblastomas (lanes 1–5), two (lanes 3 and 5) show a mutation. DNA from the normal brain served as a control, both denatured (lane 6) and normal (double-stranded, lane 7) (reproduced in part from [1], permitted).