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Vranic, Semir, MD, PhD; Marchiò, Caterina, MD, PhD; Castellano, Isabella, MD; Botta, Cristina, BSc; Scalzo, Maria Stella, BSc; Bender, Ryan P., PhD; Payan-Gomez, Cesar, MD, PhD; di Cantogno, Ludovica Verdun, BSc; Gugliotta, Patrizia, MSc; Tondat, Fabrizio, PhD; di Celle, Paola Francia, PhD; Mariani, Sara, MSc; Gatalica, Zoran, MD, DSc; Sapino, Anna, MD
Human pathology, 09/2015, Letnik: 46, Številka: 9Journal Article
Summary Despite the marked improvement in the understanding of molecular mechanisms and classification of apocrine carcinoma, little is known about its specific molecular genetic alterations and potentially targetable biomarkers. In this study, we explored immunohistochemical and molecular genetic characteristics of 37 invasive apocrine carcinomas using immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), and next-generation sequencing (NGS) assays. IHC revealed frequent E-cadherin expression (89%), moderate (16%) proliferation activity Ki-67, phosphohistone H3, infrequent (~10%) expression of basal cell markers CK5/6, CK14, p63, caveolin-1, loss of PTEN (83%), and overexpression of HER2 (32%), EGFR (41%), cyclin D1 (50%), and MUC-1 (88%). MLPA assay revealed gene copy gains of MYC , CCND1 , ZNF703 , CDH1 , and TRAF4 in 50% or greater of the apocrine carcinomas, whereas gene copy losses frequently affected BRCA2 (75%), ADAM9 (54%), and BRCA1 (46%). HER2 gain, detected by MLPA in 38% of the cases, was in excellent concordance with HER2 results obtained by IHC/FISH ( κ = 0.915, P < .001). TOP2A gain was observed in one case, while five cases (21%) exhibited TOP2A loss. Unsupervised hierarchical cluster analysis revealed two distinct clusters: HER2- positive and HER2- negative ( P = .03 and .04, respectively). NGS assay revealed mutations of the TP53 (2 of 7, 29%), BRAF/KRAS (2 of 7, 29%), and PI3KCA/PTEN genes (7 of 7, 100%). We conclude that morphologically defined apocrine carcinomas exhibit complex molecular genetic alterations that are consistent with the “luminal-complex” phenotype. Some of the identified molecular targets are promising biomarkers; however, functional studies are needed to prove these observations.
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