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.
Highlights
Chordoma is an uncommon malignant neoplasm with notochord differentiation that most often arises in the axial skeleton
Chordoma Cases Frozen tumor specimens were obtained from 20 patients including 14 males and 6 females who ranged in age from 41 to 83 years
All tumors were classified as conventional, sporadic chordomas by light microscopy except for one neoplasm which was diagnosed as a chondroid subtype (CH9)
Summary
Chordoma is an uncommon malignant neoplasm with notochord differentiation that most often arises in the axial skeleton. Chordoma has a long clinical course as it is typically slow growing; metastases tend to develop years after initial diagnosis. Regardless, it is often locally aggressive, and has a high rate of recurrence when not widely excised. The morphology and immunoprofile of chordoma is well recognized, the genetic mechanisms underlying the development of the tumor have not been fully characterized. Understanding these processes is important as they govern the biological behavior of the neoplasm and may harbor potential relevant targets for therapy
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