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 at least three cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. Our findings highlight the value of screening for complex genomic rearrangements in searches for cancer-susceptibility genes.

Figure 1

Duplications of 6q27 region in chordoma cases from Families 1, 3, 4, and 8 by the custom fine-tiling CGH array. Each point represents an average of 40 oligonucleotide probes. Duplications in chordoma cases from the four families were determined by elevated log2 ratios which are shown by red horizontal bars. The segmental duplication in Family 3 is complex; probe intensities suggest a short genomic interval with normal copy number at approximately chr6:166,200,000; segments toward the telomeric end of the rearrangement have intensities suggesting triplication. The commonly amplified region in all four families is about 100 kb in size and contains only one gene, the T gene. There were no previously reported CNVs, as shown by pink bars, in the T gene region.