To better understand the timing for presentation of allelic losses in human breast carcinogenesis, we compared the allelotypic profile of 23 in situ ductal carcinomas with that of 29 invasive ductal carcinomas. We also compared the allelotype of the invasive ductal breast carcinomas with that of 23 invasive lobular breast carcinomas. These studies were performed by means of microsatellite length polymorphisms from microdissected paraffin sections. We observed that involvement of chromosome arms 1p, 3p, 3q, 6p, 16p, 18p, 18q, 22q, and possibly 6q and 11p appear to be late events in breast cancer progression because allelic losses or imbalances affecting these areas were observed with very low frequency at the in situ stage. On the other hand, allelic imbalances and losses affecting chromosome arms 7p, 16q, 17p, and 17q appear to be early abnormalities because they were observed in approximately 25–30% of ductal carcinoma in situ lesions. Allelic losses and imbalances affecting the 8p arm were frequently observed in invasive lobular breast carcinomas. It was also interesting that microsatellite instability, also known as replication error (RER) phenotype, was found to occur at a high frequency in invasive lobular breast carcinomas because 9 of 23 (39%) were RER+, compared with 7 of 52 (13.5%) RER+ of breast cancers with ductal differentiation (P = 0.012, x2 test). Our findings provide for the first time molecular evidence suggesting that invasive lobular breast carcinomas may arise by a different mechanism of carcinogenesis than ductal carcinomas.

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This work was supported by United States Army Breast Cancer Program Grant DAMD 17-94-J-4078 (C. M. A.) and in part by NIH Grant R01 CA59967 (C. M. A.) and a University Cancer Foundation matching supplement.

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