Mapping loss of heterozygosity in normal human breast cells from BRCA1/2 carriers

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.

Germline copy number variations in BRCA1‐associated ovarian cancer patients

“…2). Previous studies using low-resolution genetic analysis reported that allelic imbalance is increased threefold in normal breast epithelium from BRCA1 mutation carriers, compared to controls (Larson et al, 2005;Clarke et al, 2006). Recently, Rennstam et al (2010) used high-resolution arraybased comparative genomic hybridization to show that genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers are more frequent than in the normal breast tissue of age-matched controls.…”

Genetic Predisposition Directs Breast Cancer Phenotype by Dictating Progenitor Cell Fate

“…Furthermore, LOH is a stochastic event in BRCA1 mut/+ patients, affecting the mutant or wild-type alleles at similar frequencies (Clarke et al, 2006). Since the analysis of prophylactic mastectomy tissues showed differentiation defects in significant proportions of the breast tissue, this suggests that LOH was not likely responsible for the perturbations in breast epithelial differentiation or basal tumor phenotype.…”

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele

“…Although this is the first report on the loss of the Mutp53 allele through LOH in an apparent healthy tissue, Mut-LOH was noticed for other TSGs with a role in DNA repair. [41][42][43][44][45] It is tempting to speculate that LOH can be seen as a physiological genetic repair mechanism. Gene expression, copy number and sequencing analyses (Figures 6f, 2e, f and h) point to the induction of HRDRP events as the mechanism underlie most cases of LOH.…”