T (brachyury) gene duplication confers major susceptibility to familial chordoma

Abstract

Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with ≥ 3 cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T gene (Brachyury), which plays an important role in notochord development and is expressed in most sporadic chordomas. Our findings highlight the need to include screening for complex genomic rearrangements in searches for cancer susceptibility genes.

ΔNp63 transcriptionally regulatesbrachyury, a gene with diverse roles in limb development, tumorigenesis and metastasis

“…Importantly, brachyury is highly expressed in chordoid cancer cells, chordoma and chondrosarcoma, a malignant bone tumor originating in the cartilage. 22,25 Chordoid cells are those that resemble notochordal tissue. Because brachyury is essential for notochord formation and differentiation, misexpression or overexpression of brachyury can lead to the formation of tumors with chordoid features.…”

“…Brachyury also regulates epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), which in addition to being critical processes in development are also involved in tumor metastasis. [20][21][22] Recently, the phenotypes of the p63 mutant mice are complex and diverse. the p63 -/-mice develop severe defects in morphogenesis of ectodermal appendages, and p63 +/-mice are tumor prone.…”

“…19 Interestingly, brachyury plays diverse roles in biology with critical functions during embryonic development and in tumorigenesis. [20][21][22] The apical ectodermal ridge (AER) is a thickened ridge of ectoderm that is essential for limb morphogenesis. 23,24 Brachyury is expressed in the mesoderm at the onset of limb formation, and mice mutant for brachyury exhibit a disruption in AER morphogenesis.…”

“…Using two distinct antibodies for p63, brachyury has been shown to be upregulated in a variety of tumors and tumor cell lines, including those of the small intestine, stomach, kidney, bladder, uterus, ovary, testis, lung, colon and prostate, 21 and chordoma, a rare malignant bone tumor. 22,25 The p63 mutant mice display multiple defects including failure of proper limb formation and tumor formation in heterozygous mice.…”

“…1,30 Additionally, other studies indicate that brachyury is also highly expressed in several human cancers. 21,22,25 To ask whether ∆Np63 expression correlates with brachyury expression in tumors, we performed q-RT PCR using tumor cell lines from p53 +/-and p53 +/-;p63 +/-mice with varying levels of ∆Np63 (Fig. 4A).…”