title: Recurrent chromosomal copy number alterations in sporadic chordomas.
abstract: The molecular events in chordoma pathogenesis have not been fully delineated, particularly with respect to copy number changes. Understanding copy number alterations in chordoma may reveal critical disease mechanisms that could be exploited for tumor classification and therapy. We report the copy number analysis of 21 sporadic chordomas using array comparative genomic hybridization (CGH). Recurrent copy changes were further evaluated with immunohistochemistry, methylation specific PCR, and quantitative real-time PCR. Similar to previous findings, large copy number losses, involving chromosomes 1p, 3, 4, 9, 10, 13, 14, and 18, were more common than copy number gains. Loss of CDKN2A with or without loss of CDKN2B on 9p21.3 was observed in 16/20 (80%) unique cases of which six (30%) showed homozygous deletions ranging from 76 kilobases to 4.7 megabases. One copy loss of the 10q23.31 region which encodes PTEN was found in 16/20 (80%) cases. Loss of CDKN2A and PTEN expression in the majority of cases was not attributed to promoter methylation. Our sporadic chordoma cases did not show hotspot point mutations in some common cancer gene targets. Moreover, most of these sporadic tumors are not associated with T (brachyury) duplication or amplification. Deficiency of CDKN2A and PTEN expression, although shared across many other different types of tumors, likely represents a key aspect of chordoma pathogenesis. Sporadic chordomas may rely on mechanisms other than copy number gain if they indeed exploit T/brachyury for proliferation.
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. lple@partners.org
authors: Long Phi
authors: LP
authors: Le
authors: G Petur
authors: GP
authors: Nielsen
authors: Andrew Eric
authors: AE
authors: Rosenberg
authors: Dafydd
authors: D
authors: Thomas
authors: Julie M
authors: JM
authors: Batten
authors: Vikram
authors: V
authors: Deshpande
authors: Joseph
authors: J
authors: Schwab
authors: Zhenfeng
authors: Z
authors: Duan
authors: Ramnik J
authors: RJ
authors: Xavier
authors: Francis J
authors: FJ
authors: Hornicek
authors: A John
authors: AJ
authors: Iafrate
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