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Dr Paul Edwards

Dr Paul Edwards

Reader in Cancer Biology (retired)

Division of Cellular and Molecular Pathology

Rearrangements of the genome in breast and oesophageal cancer.

Cancer Research UK Cambridge Institute
Addenbrooke's Site
Hills Road
Cambridge

Research themes

Genomics:

Research Interests

Edwards Research

For over 20 years we have focused on the role of rearrangements of large segments of the genome, i.e. chromosome translocations, duplications, deletions and inversions, in the common cancers such as breast cancer (reviewed in Edwards,  J Pathol 2010;220:244-54). These have proved particularly difficult to analyse in the common cancers, but they are abundant and have powerful effects, particularly where they create fusion genes—genes formed by fusion of two genes, like the BCR-ABL fusion of chronic myeloid leukaemia.  We estimated from transcriptome data that an average breast cancer expresses 10 fusion genes (Edwards & Howarth. Breast Cancer Research 2012;14, 303).

A good starting point to understand genome rearrangements at the largest scale is the multicolour fluorescent ‘SKY’ images like the one shown here, which outline the major chromosome translocations in a tumour (see our catalogue at http://www.pawefish.path.cam.ac.uk). To map the boundaries of the chromosome segments seen in these images, we first used ‘array painting’, in which individual chromosomes are separated in a cell sorter and then analyzed by hybridization to DNA microarrays (Howarth et al, 2008). During the course of this we found that reciprocal translocations often have tens of kilobases of common sequence duplicated onto both product chromosomes, leading us to propose that chromosome translocations are formed at replication bubbles (Howarth et al, 2011).  More recently we have moved to ‘paired end sequencing’ methods, which exploit massively-parallel DNA sequencing (Edwards, 2010). This strategy identifies rearrangements by finding the junctions between rearranged bits of DNA. We were able to use knowledge of genome evolution in breast cancers to distinguish early and late mutations (Newman et al, 2013).

In addition to work on breast, we are now involved in the International Genome Consortium (ICGC) project, based in Cambridge, to sequence 500 oesophageal adenocarcinomas. This is funded by Cancer Research UK and lead by Prof. Rebecca Fitzgerald (Dept Oncology and MRC Cancer Unit). This lead us to find that the oesophageal adenocarcinomas have an exceptionally high incidence of novel LINE-1 mobile element insertions, on average over 100 new inserts per tumour, which are likely to make a contribution to genetic change but remain largely uncharacterized (Paterson et al 2014).

We have also worked on methods for mapping genomes that rely on sampling: parts of the genome that are close together always turn up in the same samples. We showed that the linear form of this approach, HAPPY mapping (Dear & Cook, Nucleic Acids Res 1989;17,6795), could be used to map cancer rearrangements (Pole et al, 2011). Generalizing the approach to 3D led to development of the GAM method for mapping the arrangement of DNA in the nucleus (Beagrie et al, 2017).

Key Publications

  1. RA Beagrie, A Scialdone, M Schueler, DCA Kraemer, M Chotalia, SQ Xie, M Barbieri, I de Santiago, L-M Lavitas, MR Branco, JF, JDostie, L Game, N Dillon, PAW Edwards, M Nicodemi, A Pombo Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM) Nature 2017;543 (7646),519-524
  2. Paterson AL, Weaver JM, Eldridge MD, Tavaré S, Fitzgerald RC, Edwards PA, OCCAMs Consortium. Mobile element insertions are frequent in oesophageal adenocarcinomas and can mislead paired-end sequencing analysis . BMC Genomics.2015, 16:473
  3. Newman S , Howarth KD, Greenman CD, Bignell GR, Tavaré S, Edwards PAW. (2013) The relative timing of mutations in a breast cancer genome. PLoS ONE. 2013;8:e64991.
  4. Pole JCM, McCaughan F, Newman S, Howarth KD, Dear PH, Edwards PAW. Single-molecule mapping of genome rearrangements in cancer. Nucleic Acids Res. 2011; doi: 10.1093/nar/gkr227
  5. Howarth KD, Pole JCM, Beavis JC, Batty EM, Newman S, Bignell GR, Edwards PAW. Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles. Genome Research 2011; 21 525-534