Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast

The clonal nature of neoplastic lesions such as invasive breast cancer and ductal carcinoma in situ (DCIS) has been widely proven by several prolifera tive, genetic or other malignancy-associated markers. The aim of this study is to clarify whether benign hyperplastic lesions such as ductal hyperplas ia of usual type (DH) and papilloma can be distinguished from neoplastic le sions such as DCIS by X-chromosome inactivation analysis. Clonal analysis w as performed using a polymerase chain reaction-based assay for non-random X -chromosome inactivation of the human androgen receptor gene (HUMARA). Form alin-fixed and paraffin-embedded archival tissue of ten DCIS, sixteen DH, n ine papillomas, and seven normal terminal ductal lobular units (TDLUs) was laser-microdissected to avoid contamination with surrounding tissue. All of the cases analysed revealed a monoclonal origin. Furthermore, in one of th ese cases, opposite X chromosomes were inactivated within the same breast. X-linked inactivation analysis clearly demonstrates that, at least in the b reast, monoclonality is not restricted to neoplastic processes. The data su pport the hypothesis that the mammary gland is organized into distinct stem cell-derived monoclonal patches and that TDLUs are monoclonal in origin. A ny proliferative lesion arising within such a pre-existing clonal patch sho uld therefore be clonal, irrespective of whether it originates from one or more patch cells. Thus, X-chromosome inactivation analysis cannot be consid ered a valid I method far distinguishing between neoplastic and hyperplasti c breast lesions. Copyright (C) 2000 John Wiley & Sons, Ltd.