TBXT – Chordoma

Chordoma is a rare malignant bone neoplasm arising from notochordal remnants along the neuraxis. The T-box transcription factor gene TBXT encodes Brachyury, a critical regulator of notochord development and epithelial-to-mesenchymal transition in carcinoma. Overexpression and genomic duplications of TBXT have been implicated as major drivers of both familial and sporadic chordoma.

In a landmark study, high-resolution array-CGH identified unique germline duplications of the TBXT locus on 6q27 in four multiplex families with at least three affected members, co-segregating with disease across at least 12 probands ([PMID:19801981]). Subsequent sequencing of all TBXT exons in 24 familial and 103 sporadic chordoma cases confirmed a significant association of the common variant rs2305089 with increased risk (familial OR = 2.6, P = 0.067; sporadic OR = 2.85, P < 0.0001) and identified two additional SNPs (rs1056048, rs3816300) enriched in familial and early-onset patients ([PMID:24990759]).

In a cohort of 104 sporadic chordomas, somatic duplications of TBXT mirroring the germline architecture were detected in 27% of cases, establishing TBXT amplification as a recurrent somatic driver ([PMID:29026114]).

Functional interrogation using the JHC7 chordoma cell line, derived from a primary sacral tumor with TBXT copy gain, demonstrated stable Brachyury expression in vitro and in xenografts. shRNA-mediated silencing of TBXT induced complete growth arrest, senescence, and loss of serial passaging, confirming tumor dependency on Brachyury ([PMID:21699479]).

These genetic and experimental data support a dosage-dependent gain-of-function mechanism for TBXT in chordoma pathogenesis. Screening for germline and somatic TBXT duplications is clinically actionable for diagnosis and familial risk assessment, and targeted TBXT inhibition represents a promising therapeutic approach.

Key take-home: TBXT duplications underlie a definitive autosomal dominant predisposition to chordoma and drive tumor growth through Brachyury-dependent mechanisms.

References

• Nature Genetics • 2009 • T (brachyury) gene duplication confers major susceptibility to familial chordoma. PMID:19801981
• Human Genetics • 2014 • Characterization of T gene sequence variants and germline duplications in familial and sporadic chordoma. PMID:24990759
• Nature Communications • 2017 • The driver landscape of sporadic chordoma. PMID:29026114
• Journal of Neurosurgery • 2011 • Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target. PMID:21699479

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