Chromosome translocations in breast cancer

Background

Genome rearrangement is a major mechanism of gene alteration in cancer. Chromosome translocations and inversions can result in gene fusion, promoter insertion or gene inactivation. In the past it has been assumed that such rearrangements are not significant players in the common epithelial cancers, as they are in leukaemias and sarcomas. However, this view is now being challenged. In particular, Tomlins and colleagues found that around 70% of prostate cancers have translocations or inversions of the ETS family of transcription factors [1]. In breast cancer, we have shown that the NRG1/heregulin gene is translocated in 6% of primary cases [2] and Soda and colleagues described fusions of ALK in 7% of lung cancers [3].

Methods and results

We present a comprehensive analysis by array painting of the chromosome translocations of breast cancer cell lines HCC1806, HCC1187 and ZR-75-30. In array painting, chromosomes are isolated by flow cytometry, amplified and hybridized to DNA microarrays [4]. A total of 200 breakpoints were identified and all were mapped to 1 Mb resolution on BAC arrays, then 40 selected breakpoints, including all balanced breakpoints, were further mapped on tiling-path BAC arrays or to around 2 kb resolution using oligonucleotide arrays. Many more of the translocations were balanced than expected, either reciprocal (eight in total) or balanced for at least one participating chromosome (19 paired breakpoints). Many breakpoints were at genes that are plausible targets of oncogenic translocation, including CTCF and P300. Two gene fusions were also demonstrated, TAX1BP1-AHCY and RIF1-PKD1L1.

Conclusion

Our data establish that array painting is a very effective way to map substantial numbers of translocation breakpoints and support the emerging view that chromosome rearrangements that fuse, activate or otherwise alter genes at their breakpoints may play an important role in common epithelial cancers.