Paul A.W. Edwards

Hutchison/MRC Research Centre, Box 197 Addenbrooke's Hospital, Cambridge CB2 0XZ,

and

Division of Molecular Cellular Pathology, Department of Pathology, University of Cambridge

Research Interests Chromosome Rearrangements in Breast Cancer
Current Focus Chromosome rearrangements, such as translocations, inversions and deletions, are frequent in common cancers such as breast, prostate and colorectal carcinoma. A typical breast cancer will have 10 to 20 chromosome aberrations. It has been fashionable until recently to dismiss these as noise, or merely resulting in LOH (loss of heterozygosity), but it is now clear that some of these chromosome rearrangements create fusion genes, just as happens in leukaemias. The most dramatic evidence for this was the discovery that most prostate cancers have inversions and translocations of ETS-family transcription factors [1]. We are now finding fusion genes in breast cancer.

Our research is aimed at finding fusion genes in breast cancers, through a comprehensive analysis of the chromosome aberrations in a series of breast cancer cell lines, to the level of individual genes. We principally use 'array painting' [2], in which chromosomes are purified in a fluorescence-activated cell sorter and hybridized to DNA microarrays—a combination of reverse chromosome painting and array CGH. Using high-resolution arrays we can map breakpoints to a few kb. These are backed up by a variety of FISH techniques. We have recently started to use high-throughput sequencing as described in [5].

Our recent work has uncovered several gene fusions [2] and interesting genes broken by translocations in breast cancer cell lines. We also described recurring breaks in the cancer-critical gene NRG1 in at least 6% of breast cancers [3], which we found in collaboration with colleagues in Marseilles. NRG1 is on the short arm of chromosome 8, 8p, and encodes the heregulins, growth factor proteins that bind to members of the EGF-receptor/HER2/ErbB2 family of receptors already known to play an important role in breast and other common cancers. As 8p is frequently lost in cancers, and the losses almost all include complete or parial loss of the NRG1 gene [4], breaks in NRG1 might inactivate rather than activate the gene [Chua, Y-L et al, submitted].
Previous Work We previously obtained outline karyotypes of a large number of epithelial cancer cell lines by 24-colour chromosome painting (FISH), using the technique of Spectral Imaging or 'SKY'. The image top right is a metaphase from this study. A catalogue of the resulting (SKY) karyotypes is available on a separate website, together with various supplementary data. We have also characterised rearrangements and amplifications of 8p, the short arm of chromosome 8 (see [4] and publications).

A previous programme of this lab was to try to understand what cancer mutations do to the three-dimensional growth pattern of the mammary gland.
[1] Tomlins et al, Science 2005; 310: 644-8

[2] Howarth, KD, Blood, KA, Ng, BL, Beavis, JC, Chua, Y, Cooke, SL, Raby, S, Ichimura, K, Collins, VP, Carter, NP, Edwards, PA. Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes. Oncogene 2008;27(23):3345-59

[3] Huang, HE, Chin, SF, Ginestier, C, Bardou, VJ, Adelaide, J, Iyer, NG, Garcia, MJ, Pole, JC, Callagy, GM, Hewitt, SM, Gullick, WJ, Jacquemier, J, Caldas, C, Chaffanet, M, Birnbaum, D, Edwards, PA. A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene. Cancer Res 2004;64:6840-4

[4] Pole, JC, Courtay-Cahen, C, Garcia, MJ, Blood, KA, Cooke, SL, Alsop, AE, Tse, DM, Caldas, C, Edwards, PA. High-resolution analysis of chromosome rearrangements on 8p in breast, colon and pancreatic cancer reveals a complex pattern of loss, gain and translocation. Oncogene 2006;25(41):5693-706-8

[5] 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. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet 2008
pawe 1@cam.ac.uk +44 (0)1223 763338 Aug 2008

Current Research Interests

Catalogue of SKY Karyotypes

Publications

Postgraduate Studentships

Positions Available - Post Docs etc