Identification of typical medullary breast carcinoma as a genomic sub-group of basal-like carcinomas, a heterogeneous new molecular entity

Typical medullary breast carcinoma (MBC) has recently been recognized to be part of the basal-like carcinoma spectrum, a feature in agreement with the high rate of TP53mutations previously reported in MBCs. The present study was therefore designed to identify phenotypic and genetic alterations that distinguish MBCs from basal-like carcinomas (BLC). Expression levels of estrogen receptor (ER), progesterone receptor (PR), ERBB2, TP53, cytokeratins (KRTs) 5/6, 14, 8/18, epidermal growth factor receptor and KIT, as well as TP53gene sequence and high-density array comparative genomic hybridization (CGH) profiles, were assessed and compared in a series of 33 MBCs and 26 BLCs. All tumors were negative for ER, PR and ERBB2. KRTs 5/6 were more frequently expressed in MBCs (94%) than in BLCs (56%) (p= 0.0004). TP53mutations were disclosed in 20/26 MBCs (77%) and 20/24 BLCs (83%). Array CGH analysis showed that a higher number of gains (95 regions) and losses (34 regions) was observed in MBCs than in BLCs (36 regions of gain; 13 regions of losses). In addition, gains of 1q and 8q, and losses of X were found to be common to the two groups, whereas gains of 10p (53% of the cases), 9p (30.8% of the cases) and 16q (25.8% of the cases), and losses of 4p (34.8% of the cases), and amplicons of 1q, 8p, 10p and 12p were the genetic alterations found to characterize MBC. Our study has revealed that MBCs are part of the basal-like group and share common genomic alterations with BLCs, the most frequent being 1q and 8q gains and X losses; however, MBCs are a distinct entity within the basal-like spectrum, characterized by a higher rate of KRT 5/6 expression, a higher rate of gains and losses than BLCs, recurrent 10p, 9p and 16q gains, 4p losses, and 1q, 8p, 10p and 12p amplicons. Our results thus contribute to a better understanding of the heterogeneity in basal-like breast tumors and provide potential diagnostic tools.