High-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis

dc.contributor.authorDiaz, Roberto Jose
dc.contributor.authorGuduk, Mustafa
dc.contributor.authorRomagnuolo, Rocco
dc.contributor.authorSmith, Christian A.
dc.contributor.authorNorthcott, Paul
dc.contributor.authorShih, David
dc.contributor.authorBerisha, Fitim
dc.contributor.authorFlanagan, Adrienne
dc.contributor.authorMunoz, David G.
dc.contributor.authorCusimano, Michael D.
dc.contributor.authorPamir, M. Necmettin
dc.contributor.authorRutka, James T.
dc.date.accessioned2023-02-21T12:39:55Z
dc.date.available2023-02-21T12:39:55Z
dc.date.issued2012-01-01
dc.description.abstractChordoma is a rare tumor arising in the sacrum, clivus, or vertebrae. It is often not completely resectable and shows a high incidence of recurrence and progression with shortened patient survival and impaired quality of life. Chemo-therapeutic options are limited to investigational therapies at present. Therefore, adjuvant therapy for control of tumor recurrence and progression is of great interest, especially in skull base lesions where complete tumor resection is often not possible because of the proximity of cranial nerves. To understand the extent of genetic instability and associated chromosomal and gene losses or gains in skull base chordoma, we undertook whole-genome single-nucleotide polymorphism microarray analysis of flash frozen surgical chordoma specimens, 21 from the clivus and 1 from C1 to C2 vertebrae. We confirm the presence of a deletion at 9p involving CDKN2A, CDKN2B, and MTAP but at a much lower rate (22\%) than previously reported for sacral chordoma. At a similar frequency (21\%), we found aneuploidy of chromosome 3. Tissue microarray immunohistochemistry demonstrated absent or reduced fragile histidine triad (FHIT) protein expression in 98\% of sacral chordomas and 67\% of skull base chordomas. Our data suggest that chromosome 3 aneuploidy and epigenetic regulation of FHIT contribute to loss of the FHIT tumor suppressor in chordoma. The finding that FHIT is lost in a majority of chordomas provides new insight into chordoma pathogenesis and points to a potential new therapeutic target for this challenging neoplasm. Neoplasia (2012) 14, 788-798
dc.description.issue9
dc.description.issueSEP
dc.description.pages788-U141
dc.description.volume14
dc.identifier.doi10.1593/neo.12526
dc.identifier.urihttps://hdl.handle.net/11443/2558
dc.identifier.urihttp://dx.doi.org/10.1593/neo.12526
dc.identifier.wosWOS:000313345200002
dc.publisherNEOPLASIA PRESS
dc.relation.ispartofNEOPLASIA
dc.titleHigh-resolution Whole-Genome Analysis of Skull Base Chordomas Implicates FHIT Loss in Chordoma Pathogenesis
dc.typeArticle
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