Paul Edwards

Chromosome rearrangements in breast cancers

Chromosomes of breast cancer cell line HCC1187. Each colour represents material from a particular normal chromosome.

Chromosome rearrangements, such as translocations, inversions and deletions, are frequent in common cancers such as breast, colorectal and prostate carcinoma (as shown in the first image), but until recently they have attracted little interest. Some of these, like chromosome translocations found in leukaemias, will fuse genes or activate genes by promoter insertion, creating powerful oncogenic events. The most dramatic example to date is the TMPRSS2-ERG gene fusion which is present in more than half of all malignant prostate tumours (Tomlins et al, Science 2005; 310:644).

Mapping a chromosome translocation between chromosomes 1 and 8 by 'array painting'. The chromosome (left) is purified in a cell sorter, and its DNA hybridzed to a custom high-resolution DNA microarray. The sharp steps in hybridization signal (y axis) identify the breakpoints on chromosome 1 (middle) and 8 (right) to about 1000 base pairs resolution.

Our long-term aim is a comprehensive analysis of chromosome rearrangements in breast cancer. Currently we are mapping translocations in cell lines to the gene level, using a range of techniques, including chromosome isolation (sorting chromosomes in a cell sorter), hybridization to DNA microarrays, fluorescent staining of chromosomes (fluorescence in situ hybridization or FISH), and high-throughput sequencing on the Solexa/Illumina sequencing platform. Combining chromosome isolation with hybridization to arrays gives the technique 'array painting' (middle image), which we have used to completely analyse the chromosome translocations and deletions in four breast cancer lines [Howarth et al, 2008 and unpublished]. FISH on tissue sections of tumours then allows us to look for breaks in the same genes in panels of breast cancers (lower image). Most recently we have started to use high-throughput sequencing to speed up discovery of rearrangements. We use 'paired end reads', breaking the genome into fragments of precise size and sequencing their ends, to find places in the genome which have been rearranged [Campbell et al, 2008].

Detecting chromosome translocations in sections of breast cancer (FISH on paraffin sections). Normal chromosomes show red and green together, translocated ones show red alone.

We have already found a number of gene fusions that are expressed in breast cancer cell lines-one line has at least five-and there will be many more. At least some of the genes broken in these rearrangements are broken in breast tumours, i.e. not just in cell lines. So it looks as though gene rearrangement will prove to be a major contributor to breast cancer development.

Contact:

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Recent publications

Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles. Howarth KD, Pole JC, Beavis JC, Batty EM, Newman S, Bignell GR, Edwards PA. Genome Res. 2011 Apr;21(4):525-34.

High-throughput analysis of chromosome translocations and other genome rearrangements in epithelial cancers. Newman S, Edwards PA. Genome Med. 2010 Mar 17;2(3):19.

The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Chua YL, Ito Y, Pole JC, Newman S, Chin SF, Stein RC, Ellis IO, Caldas C, O'Hare MJ, Murrell A, Edwards PA. Oncogene. 2009 Nov 19;28(46):4041-52.

High-resolution array CGH clarifies events occurring on 8p in carcinogenesis. Cooke SL, Pole JC, Chin SF, Ellis IO, Caldas C, Edwards PA. BMC Cancer. 2008 Oct 7;8:288.

Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T, Stebbings LA, Leroy C, Edkins S, Hardy C, Teague JW, Menzies A, Goodhead I, Turner DJ, Clee CM, Quail MA, Cox A, Brown C, Durbin R, Hurles ME, Edwards PA, Bignell GR, Stratton MR, Futreal PA. Nat Genet. 2008 Jun;40(6):722-9.

To undertake world leading research into cancer cell biology that can be translated into clinical practice to improve the diagnosis and treatment of cancers.