Chordoma and chondrosarcoma gene profile: implications for immunotherapy

Abstract

Chordoma and chondrosarcoma are malignant bone tumors characterized by the abundant production of extracellular matrix. The resistance of these tumors to conventional therapeutic modalities has prompted us to delineate the gene expression profile of these two tumor types, with the expectation to identify potential molecular therapeutic targets. Furthermore the transcriptional profile of chordomas and chrondrosarcomas was compared to a wide variety of sarcomas as well as to that of normal tissues of similar lineage, to determine whether they express unique gene signatures among other tumors of mesenchymal origin, and to identify changes associated with malignant transformation. A HG-U133A Affymetrix Chip platform was used to determine the gene expression signature in 6 chordoma and 14 chondrosarcoma lesions. Validation of selected genes was performed by qPCR and immunohistochemistry (IHC) on an extended subset of tumors. By unsupervised clustering, chordoma and chondrosarcoma tumors grouped together in a genomic cluster distinct from that of other sarcoma types. They shared overexpression of many extracellular matrix genes including aggrecan, type II & X collagen, fibronectin, matrillin 3, high molecular weight-melanoma associated antigen (HMW-MAA), matrix metalloproteinase MMP-9, and MMP-19. In contrast, T Brachyury and CD24 were selectively expressed in chordomas, as were Keratin 8,13,15,18 and 19. Chondrosarcomas are distinguished by high expression of type IX and XI collagen. Because of its potential usefulness as a target for immunotherapy, the expression of HMW-MAA was analyzed by IHC and was detected in 62% of chordomas and 48% of chondrosarcomas, respectively. Furthermore, western blotting analysis showed that HMW-MAA synthesized by chordoma cell lines has a structure similar to that of the antigen synthesized by melanoma cells. In conclusion, chordomas and chondrosarcomas share a similar gene expression profile of up-regulated extracellular matrix genes. HMW-MAA represents a potential useful target to apply immunotherapy to these tumors.

Genomic Profiling of Chondrosarcoma: Chromosomal Patterns in Central and Peripheral Tumors

“…A recurrent amplicon was also identified in 11q22.1-q22.3, affecting a region harboring a cluster of MMP genes. These genes encode matrix metalloproteinases, and interestingly, 3 of the genes in the cluster (MMP3, MMP7, and MMP13) have recently been shown to be highly expressed in chondrosarcoma (30).…”

The molecular aspects of chordoma

“…The high molecular weight melanoma-associated antigen (HMW-MAA) is a human membrane-bound protein often overexpressed in melanoma and has a role in invasion and cell migration. The expression of HMW-MAA, also known as chondroitin sulphate proteoglycan 4 (CSPG4), was detected in 62 % of 21 chordomas in one study [96]. Scheil-Bertram and colleagues recently carried out a molecular profiling study of chordomas to compare the transcriptional expression profile of one sacral chordoma recurrence, two chordoma cell lines (U-CH1 and U-CH2), and one chondrosarcoma cell line (U-CS2) with a vertebral disc using a high-density oligonucleotide array.…”

The Next Step: Innovative Molecular Targeted Therapies for Treatment of Intracranial Chordoma Patients

“…Schwab and colleagues 11 performed gene chip analysis on 6 chordomas and found a number of chordoma-specific expression patterns, notably that T-Brachyury and CD24 were selectively expressed in chordomas, as were keratin 8,13,15,18 and 19. The T-Brachyury gene has been explored in more detail by Yang and colleagues, who linked mutations in this gene in 4 different multiplex chordoma families, suggesting that this gene, differentially upregulated in the developing notochord, deserves significant further investigation.…”