title: High-resolution whole-genome analysis of skull base chordomas implicates FHIT loss in chordoma pathogenesis.
abstract: Chordoma 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. Chemotherapeutic 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.
authors.affiliation: Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Roberto Jose
authors.initials: RJ
authors.lastname: Diaz
authors.forename: Mustafa
authors.initials: M
authors.lastname: Guduk
authors.forename: Rocco
authors.initials: R
authors.lastname: Romagnuolo
authors.forename: Christian A
authors.initials: CA
authors.lastname: Smith
authors.forename: Paul
authors.initials: P
authors.lastname: Northcott
authors.forename: David
authors.initials: D
authors.lastname: Shih
authors.forename: Fitim
authors.initials: F
authors.lastname: Berisha
authors.forename: Adrienne
authors.initials: A
authors.lastname: Flanagan
authors.forename: David G
authors.initials: DG
authors.lastname: Munoz
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cusimano
authors.forename: M Necmettin
authors.initials: MN
authors.lastname: Pamir
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002648:Child; D002817:Chordoma / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D019292:Skull Base Neoplasms / Q000235:genetics*; D055815:Young Adult; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase