1. ¹Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK
2. ²Department of Surgery, University College London, Charles Bell House, 67-73 Riding House Street, London W1W 7EJ, UK

Correspondence: Professor SR Lakhani, E-mail: s.lakhani@uq.edu.au

³Current address: Molecular & Cellular Pathology, Mayne Medical School, University of Queensland, Queensland Institute of Medical Research and Royal Brisbane and Women's Hospital, Brisbane, QLD 4006, Australia.

⁴Current address: Department of Tumour Biology, Bart's & The London, Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.

Received 6 March 2006; Revised 15 June 2006; Accepted 29 June 2006; Published online 1 August 2006.

Abstract

We have studied loss of heterozygosity at the BRCA1 and BRCA2 loci in 992 normal cell clones derived from topographically defined areas of normal tissue in four samples from BRCA1/BRCA2 mutation carriers. The frequency of loss of heterozygosity in the clones was low (1.01%), but it was found in all four samples, whether or not a tumour was present. Topographical mapping revealed that the genetic changes were clustered in some breast samples. Our study confirms the previous finding that a field of genetic instability can exist around a tumour, suggesting that sufficient tissue must be removed at surgery to avoid local recurrence. We also demonstrate that such a field of genetic change can exist in morphologically normal tissue before a tumour develops and, for the first time, we demonstrate that the field is of a size greater than one terminal duct-lobular unit. The genetic changes are not identical, however, which suggests that genetic instability in these regions may play an early role in tumour development. We also confirm and extend our original observation of loss of the wild-type BRCA1 allele in some clones, and loss of the mutant allele in others, demonstrating that loss of either allele is a stochastic event.