Brachyury, a crucial regulator of notochordal development, is a novel biomarker for chordomas

Abstract

Chordomas are malignant tumours that occur along the spine and are thought to derive from notochordal remnants. There is significant morphological variability between and within chordomas, with some showing prominent areas of chondroid differentiation. Our microarray data from a broad range of connective tissue neoplasms indicate that, at the transcriptional level, chordomas resemble cartilaginous neoplasms. Here we show that chordomas express many genes known to be involved in cartilage development, but they also uniquely express genes distinguishing them from chondroid neoplasms. The brachyury transcription factor, known to be involved in notochordal development, is only expressed by chordomas. Using a polyclonal antibody, we show that brachyury is expressed in the embryonic notochord and in all 53 chordomas analysed, labelling both chondroid and chordoid areas of these tumours. In contrast, the protein was not detected in over 300 neoplasms, including 163 chondroid tumours. Brachyury was not detected in the nucleus pulposus, arguing against the hypothesis that this tissue derives directly from the notochord. These data provide compelling evidence that chordomas derive from notochord and demonstrate that brachyury is a specific marker for the notochord and notochord-derived tumours.

Specificity of brachyury in the distinction of chordoma from clear cell renal cell carcinoma and germ cell tumors: a study of 305 cases

“…[5][6][7] Although the morphological overlap between chordoma and clear cell renal cell carcinoma is well known, we have also encountered cases in which the distinction from central nervous system germ cell tumors such as seminoma and yolk sac tumor was considered, especially in the evaluation of poorly differentiated (anaplastic) chordomas. Within the spectrum of genitourinary neoplasia, rare brachyury immunoreactivity has been reported in testicular germ cell tumors (2/14 cases; most unspecified as to subtype), including focally within non-neoplastic testis.…”

“…Brachyury immunoreactivity in renal cell carcinoma has, to the authors' knowledge, previously been studied in only one series with six cases that were all negative. 6 Particularly, given the rising incidence of metastatic renal cell carcinoma, 14,15 the increasing use of targeted therapies, and the propensity for metastasis to virtually any body site, 16,17 distinction of metastatic clear cell renal cell carcinoma from chordoma is critical. Moreover, the high incidence of bony metastasis in this study (Table 2), an incidence supported by a previous study, 16 makes metastatic clear cell renal cell carcinoma a particularly plausible morphological mimic of chordoma (both axial and extra-axial), particularly on a small biopsy sample.…”

“…Although expression of the novel antigen brachyury has come to be considered a defining diagnostic feature of chordoma, [1][2][3][4][5][6] few studies have thoroughly addressed specificity of the antibody. Chondrosarcoma, the most recognized differential diagnostic consideration for chordoma, has been thoroughly evaluated in previous studies and does not express brachyury.…”

“…Chondrosarcoma, the most recognized differential diagnostic consideration for chordoma, has been thoroughly evaluated in previous studies and does not express brachyury. 2,[5][6][7][8][9] However, within the spectrum of genitourinary neoplasia, metastatic germ cell tumors and clear cell renal cell carcinomas may also be close morphological mimics of chordoma, particularly on a small biopsy sample. Immunoreactivity with the brachyury antibody has been reported in a few germ cell tumors, either in cases without reported subtype 5 or in seminomas; 3 however, a full characterization of staining by tumor subtype has not been evaluated in a large series.…”

Frequent deletion of the CDKN2A locus in chordoma: analysis of chromosomal imbalances using array comparative genomic hybridisation

“…Usually located along the axial skeleton, primarily in the sacrococcygeal and sphenooccipital regions, chordomas are believed to be derived from remnants of the embryonal notochord (Vujovic et al, 2006). These tumours are rare lesions accounting for about 1 -4% of all primary bone sarcomas (Mirra et al, 2002).…”