Li-Fraumeni (LFS) and Li-Fraumeni-like (LFL) syndromes are associated to germline TP53 mutations, and are characterized by the development of central nervous system tumors, sarcomas, adrenocortical carcinomas, and other early-onset tumors.
Medulloblastomas, the most frequent embryonal CNS tumors, are divided into four molecularly defined groups according to the WHO 2016 Classification: wingless/integrated (WNT) signaling pathway activated, sonic hedgehog (SHH) signaling pathway activated and tumor protein p53 gene (TP53)-mutant, SHH-activated and TP53-wildtype, and non-WNT/non-SHH-activated.
Our results indicate that p53 protein is expressed in a number of central nervous system neoplasms, and suggest that in astrocytic tumors a possible association may exist between p53 protein expression and tumor progression through increasing histological grades of malignancy.
There was no relationship between bcl-2 expression and p53 gene status: approximately equal numbers of tumors with either wild-type or mutant p53 were bcl-2 negative or bcl-2 positive. bcl-2 expression is high (40-100%) among other tumors of the central nervous system which also show low malignant potential.
Alterations of the p53 protein, which is a 53 kD phosphoprotein and gene product of the p53 gene, has been found to play a major role in the genesis of a variety of human malignancies including tumors of the central nervous system.
The p53 tumor suppressor gene is frequently mutated in human cancer, and is important in the pathogenesis of other central nervous system (CNS) tumors.
Given the high accuracy and sensitivity of the yeast assay and previous negative results using conventional techniques, this indicates that p53 mutation is a rare event in non-astrocytic CNS tumor types examined here.
It remains to be shown whether this unusual pattern of CNS tumors is due to an organ-specific effect of this particular p53 mutation or whether it reflects the genetic background of the affected families.
Our results not only confirm the low penetrance of the TP53 gene on pediatric CNS tumors, but also provide further evidence of a putative tumor suppressor gene distal to TP53, between markers (D17S938, D17S926) and 17pter, specifically taking part in the development of PNET.
The observation that somatic p53 mutations in sporadic brain tumours are largely restricted to those of astrocytic origin and that astrocytomas also prevail among CNS neoplasms associated with p53 germline mutation strongly suggests, that p53 mutations are capable of initiating neoplastic transformation in astrocytes of the human nervous system.
Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group.<b>Conclusions:</b> Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system.
We and other investigators have identified deletions and mutations of the INI1 gene in the majority of rhabdoid tumors of the central nervous system, kidney, and extrarenal tissues.
CNS and extra-CNS tumors had an identical SMARCB1 amplification (n = 1) or very similar DNA methylation pattern (n = 1) suggestive of clonal origin.All patients died of tumor progression.
The loss of INI1 protein activity was first demonstrated in aggressive pediatric tumors, including atypical teratoid/rhabdoid (AT/RT) tumor of the central nervous system and malignant rhabdoid tumor of the kidney.
Cribriform neuroepithelial tumor (CRINET) is a recently recognized central nervous system neoplasm that arises in the ventricles of young children and is characterized by primitive, non-rhabdoid SMARCB1-deficient cells with prominent cribriform architecture.
The Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) has recommended that isocitrate dehydrogenase 1 and 2 wildtype (IDH1/2wt) diffuse lower-grade gliomas (LGGs) WHO grade II or III that present with a) a telomerase reverse transcriptase promoter mutation (pTERTmt), and/or b) gain of chromosome 7 combined with loss of chromosome 10, and/or c) epidermal growth factor receptor (EGFR) amplification should be reclassified as diffuse astrocytic glioma, IDH1/2-wildtype, with molecular features of glioblastoma, WHO grade IV (IDH1/2wt astrocytomas WHO IV).
Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III).