Abstract
Chordoma is a rare mesenchymal tumour of complex biology for which only histologic and immunohistochemical criteria have been defined, but no biomarkers predicting the clinical outcome and response to treatment have yet been recognised. We herein review the interdisciplinary information achieved by epidemiologists, neurosurgeons and basic scientists on chordoma, usually a sporadic tumour, which also includes a small fraction of familial cases. Main focus is on the current knowledge of the genetic alterations which might pinpoint candidate genes and molecular mechanisms shared by sporadic and familiar chordomas. Due to the scarcity of the investigated tumour specimens and the multiple chromosome abnormalities found in tumours with aberrant karyotypes, conventional cytogenetics and Fluorescence In Situ Hybridization failed to detect recurrent chordoma-specific chromosomal rearrangements. Genome-wide approaches such as Comparative Genomic Hybridization (CGH) are yet at an initial stage of application and should be implemented using BAC arrays either genome-wide or targeting selected genomic regions, disclosed by Loss of Heterozygosity (LOH) studies. An LOH region was shown by a systematic study on a consistent number of chordomas to encompass 1p36, a genomic interval where a candidate gene was suggested to reside. Despite the rarity of multiplex families with chordoma impaired linkage studies, a chordoma locus could be mapped to chromosome 7q33 by positive lod score in three independent families. The role in chordomagenesis of the Tuberous Sclerosis Complex (TSC) genes has been proved, but the extent of involvement of TSC1 and TSC2 oncosuppressors in chordoma remains to be assessed. In spite of the scarce knowledge on the genetics and molecular biology of chordoma, recent initiation of clinical trials using molecular-targeted therapy, should validate new molecular targets and predict the efficacy of a given therapy. Comparative genetic and biomolecular studies should enhance the molecular taxonomy of chordoma which might have a prognostic significance and better orient the therapeutic options.
Highlights
Chordomas are rare, low-to-intermediate grade malignant tumours which occur along the length of the craniospinal axis
They include the paired box 7 (PAX7) gene encoding a transcriptional factor expressed in the neural tube which is regulated by notochord specific signals [76], the differentially screening-selected gene aberrant in neuroblastoma (DAN), involved in the negative regulation of cell proliferation [77], the Dishevelled 1 gene (DVL1), a key factor in Wnt signalling expressed in the neural tube [78] and a few genes belonging to the tumour necrosis factor receptor superfamily (TNFRSF-1B, -8, -9, -14), the DNA fragmentation factor (DFF-A and- B) and TP73 [UCSC], all acting in apoptotic pathways
One study based on standard Comparative Genomic Hybridization (CGH) analysis has been applied and revealed a good matching with the previous cytogenetic findings [48]
Summary
It is known that in chick embryo the notochord develops through four periods of activity which are related to cytodifferentiation and functional maturation, with cessation of mitosis, cell apoptosis and decrease in the nucleolar volume in the fourth period [33] It was found by canine/bovine notochord cell cultures that a small number of notochordal cells persist in the nucleus pulposus with the function of maintaining disk integrity [34]. The results showed that 11.5% of the clivus, 5.0% of the cervical vertebrae, 0% of the thoracic vertebrae, 2.0% of the lumbar vertebrae and 12% of the sacrococcygeal vertebrae were affected These results support other evidence that classic chordomas develop from intraosseous benign notochordal cell tumours. In agreement with this view are the close histological and immunohistochemical similarities with the embryonic notochord and the correlation of chordoma development to location and incidence of notochordal vestiges [32]
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