Loss of heterozygosity in benign breast epithelium in relation to breast cancer risk.

The multistage model of breast carcinogenesis suggests that errors in DNA replication and repair generate diversity in the breast epithelium (the mutator phenotype), resulting in selection and expansion of premalignant clones with an acquired survival advantage. We measured loss of heterozygosity (LOH) in breast epithelial cells obtained by random fine-needle aspiration (FNA) biopsy from 30 asymptomatic women whose risk of breast cancer had been defined by the Gail model. Polymorphic microsatellite markers were selected on the basis of their relevance to breast cancer. Breast epithelium of 11 (37%) of 30 women had normal cytology, and that of 19 (63%) had proliferative cytology (eight with atypia and 11 without atypia). LOH was detected in two women with normal cytology and in 14 women (seven with atypia and seven without atypia) with proliferative cytology (P =.007). The frequency of LOH was associated with the cytological diagnosis, as well. The mean proportion (range) of informative markers demonstrating LOH was 0.02 (0-0.20) for the 11 women with normal cytology, as compared with 0.15 (0-0.50) for the 19 women with proliferative cytology (P =.02). Mean lifetime risk for developing breast cancer, as calculated by the Gail model, was 16.7% for women with no LOH compared with 22.9% for women with any LOH (P =.05). These observations support a multistage model of breast carcinogenesis where the initiating events are those that result in genomic instability. Accurate individualized breast cancer risk assessment may be possible based on molecular analysis of breast epithelial cells obtained by random FNA.