Ivan H. Still

Cloning of TACC1 , an embryonically expressed, potentially transforming coiled coil containing gene, from the 8p11 breast cancer amplicon

Amplification of several chromosomal regions have been observed in human breast carcinomas. One such region, 8p11, is amplified in 10 – 15% of tumor samples. Although the FGFR1 gene is located close to this region, and is often included within the amplicon, the observation that tumors exhibiting 8p11 amplification do not always overexpress FGFR1 suggests that another gene located close to FGFR1 is involved in the tumorigenic process. We now report the precise location of four expressed sequence tags (ESTs) within this region and the cloning of a novel gene, designated TACC1 (transforming acidic coiled coil gene 1), which encodes an 8 kb transcript and which is expressed at high levels during early embryogenesis. Constitutive expression of this gene under the control of the cytomegalovirus (CMV) promoter in mouse fibroblasts, results in cellular transformation and anchorage independent growth, suggesting that inappropriate expression can impart a proliferative advantage. This observation raises the possibility that amplification of TACC1 could promote malignant growth, thereby making TACC1 an attractive candidate for the gene promoting tumorigenicity as a result of the 8p11 amplification in human breast cancers.

Fine structure physical mapping of a 1·9 Mb region of chromosome 13q12

Through linkage analysis and the identification of structural chromosome rearrangements, a number of disease genes have been mapped to the pericentromeric region of the long arm of chromosome 13. Structural rearrangements, or deletions, of the 13q12 region have been implicated in a range of myeloproliferative neoplasms, and other haematopoietic malignancies. In particular, seven cases of a t(8;13) (p11; q12·1) rearrangement have been noted in patients with an atypical myeloproliferative disorder associated with T‐cell leukemia and eosinophilia. We have previously identified a CEPH megaYAC, 943E4, which crosses the translocation breakpoint in archival tumour samples from two patients with this t(8;13) translocation. As an initial step in the characterisation of this translocation breakpoint, we have generated a fine structure physical map of this 1·9 Mb YAC. We have used the method of YAC fragmentation to generate a series of deletion constructs of known size, which provide discreet physical landmarks convenient for mapping genetic markers along the 943E4 YAC. Analysis of these deletion constructs defined the order of ESTs and microsatellite markers in 943E4 as: cen‐NIB1257‐(ATP1AL1/D13S283)‐ D13S179E‐(D13S504E/D13S505E)‐D13S824E‐D13S182E‐D13S221‐tel. These markers have also been assigned to physically defined regions relative to the fragmented YAC endpoints and a derived NotI restriction map.

Characterization of the breakpoints in a t(8;13)(p11;q12) translocation from a patient with myeloproliferative disease using fluorescence in situ hybridization

We used fluorescence in situ hybridization to characterize the molecular position of the breakpoints in a t(8;13)(p11;q12) reciprocal translocation from a patient with an atypical myeloproliferative disorder. This structural chromosome abnormality is characteristic of this specific disease and occurs often as the only chromosome abnormality in the malignant cells. Yeast artificial chromosome (YAC) analysis has demonstrated that the 8p11 breakpoint lies within a region defined by YAC 959A4 and that the 13q12 breakpoint is spanned by YAC 769F9. Identifying the position of the breakpoints in this rearrangement provides the means to search for candidate genes rearranged by this highly specific structural chromosome abnormality. Genes Chromosomes Cancer 21:160–165, 1998.