p53 overexpression and mutation in metaplastic carcinoma of the breast: genetic evidence for a monoclonal origin of both the carcinomatous and the heterogeneous sarcomatous components.

Metaplastic carcinoma of the breast (MCB) is characterized by the biphasic presence of both a carcinomatous component (CC) and heterogeneous sarcomatous components (HSCs). Although an epithelial or myoepithelial origin of the HSCs has been suggested, molecular evidence for a common origin for the CC and HSCs is limited and the mechanism underlying the sarcomatous or metaplastic change is unknown. The present study investigated the frequency and nature of p53 expression and mutation in 11 biphasic and three monophasic MCBs by immunohistochemistry and either needle-assisted or laser-capture microdissection, followed by PCR and direct sequencing. In all 11 biphasic MBCs, staining for p53 was concordant in the CC and HSCs (8/11 positive and 3/11 negative), consistent with a monoclonal origin of both components. Significantly, whenever a component of carcinoma in situ was present (5/11), the p53 staining was always concordant with that in the CC and HSCs. Screening of the 14 cases for p53 mutation identified four mutants, each in a single case of biphasic MCB with concordant p53 overexpression. Both the CC and each of the HSCs revealed identical p53 mutation in all four cases; in addition, one of the four cases also had an in situ component and the same mutant was found simultaneously in the in situ, invasive, and sarcomatous components. The concordant pattern of p53 alteration (overexpression or mutation) implies that early p53 mutation, occurring prior to invasion, was maintained throughout tumour progression and metaplastic change. The findings therefore support a monoclonal histogenesis of the various components, but are neutral regarding the role of p53 alteration in the development of metaplastic change in MCBs.