Hypersensitive K303R oestrogen receptor-α variant not found in invasive carcinomas

INTRODUCTION: Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303→Arg) change in the gene encoding oestrogen receptor-α (ER-α) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. METHODS: Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. RESULTS: No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. CONCLUSION: The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-α gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment

Comparative genomic hybridization analysis of bilateral hyperplasia of usual type of the breast

Hyperplasia of usual type (HUT) is part of the spectrum of benign proliferative disease in the breast and confers an increased risk of developing invasive cancer. Its role as a putative precursor of invasive ductal carcinomas in the breast is, however, controversial. HUT is occasionally seen bilaterally but it is not clear whether there is a genetic predisposition to the process. This study has analysed 14 cases of bilateral HUT in the breast (28 independent lesions) by comparative genomic hybridization (CGH) analysis to define DNA copy number changes and to investigate any commonality in these genetic alterations. The mean number of alterations seen was 1.6 (46/28) in all lesions, with common losses at chromosomes 1p, 16p, 17q, and 22q. Bilaterally, only five alterations were seen in common across both lesions in both breasts, but no single locus was altered preferentially. These data indicate that a proportion of HUT in the breast are indeed clonal, neoplastic proliferations which exhibit genetic alterations in common with invasive breast cancer, albeit at very low levels. The limited data from these experiments do not reveal a specific predisposition locus. Copyright (C) 2003 John Wiley Sons, Ltd