Genetic alterations in 'normal' luminal and myoepithelial cells of the breast

Chromosomal loci exhibiting loss of heterozygosity (LOH) at high frequency in invasive breast cancer have been investigated in 'normal' breast tissue from patients with carcinoma and from reduction mammoplasty specimens. Duct -lobular units dissected from paraffin-embedded tissues and 485 'normal' lu minal and myoepithelial cell clones were studied, Overall, LOH was found in normal cells in 5/10 breast cancer cases and 1/3 reduction mammoplasty spe cimens, LOH was identified in normal cells adjacent to and distant from the tumour, In one case, all luminal and myoepithelial samples exhibited loss of the same allele on chromosome 13q. One case in which the patient had a g ermline truncating mutation in the BRCA1 gene exhibited LOH on 17q in 3/33 normal clones, One of these clones showed loss of wild-type allele indicati ng gene inactivation, This sample also had LOH at markers on chromosomes li p and 13q, One of 93 clones from three reduction mammoplasties showed allel e loss at a locus on chromosome 13q, The identification of LOH in breast lo bules suggests that they may be clonal, The demonstration of genetic altera tion in luminal and myoepithelial cells provides evidence for the presence of a common stem cell for the two epithelial cell types, LOH has been demon strated in normal tissues near and away from the carcinoma, suggesting that genetic alterations are likely to be more heterogeneous and widespread tha n is currently envisaged, and probably occur very early in breast developme nt. Homozygous deletion of BRCA1 per sc does not appear to provide clonal a dvantage. Copyright (C) 1999 John Wiley & Sons, Ltd.