Chromosomal alterations in pure nonneoplastic breast lesions: implications for breast cancer progression.

Introduction: Columnar cell lesions (CCL) and atypical ductal hyperplasia (ADH) frequently coexist and share molecular changes with in situ and invasive components, suggesting that CCL and ADH may be precursors to breast cancer. These conclusions are largely based on studies examining CCL and/or ADH from patients diagnosed with more advanced disease. We assessed allelic imbalance (AI) in pure CCL or ADH specimens to characterize molecular changes in nonneoplastic breast lesions.

Methods: DNA samples were obtained from laser-microdissected pure CCL (n = 42) or ADH (n = 31). AI was assessed at 26 chromosomal regions commonly altered in breast cancer. Data were analyzed using Fisher's exact and Student's t-tests using a cutoff of P < 0.05.

Results: The average AI frequency was 6.2% in CCL and 6.1% in ADH; approximately 33% of nonneoplastic lesions had no detectable genetic changes. Levels of AI in CCL and ADH were significantly (P < 0.0001) lower than observed in either low- or high-grade ductal carcinoma in situ (DCIS) lesions. Genetic changes characteristic of in situ and invasive disease, especially on chromosomes 16q and 17p, were infrequent in pure nonneoplastic lesions.

Conclusions: Pure CCL and ADH lesions demonstrate lower levels of genetic alterations than DCIS, invasive carcinomas or CCL/ADH lesions from cancerous breasts; alterations of chromosomes 16q and 17p were not detected. Pure CCL and ADH lesions are not genetically advanced, and molecular profiles do not support these lesions as obligatory precursors to more advanced disease. Molecular differences between pure and synchronous lesions support re-evaluation of current models of disease initiation, progression, and risk.