Microglandular adenosis associated with triple‐negative breast cancer is a neoplastic lesion of triple‐negative phenotype harbouring TP53 somatic mutations |
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| Authors: | Felipe C Geyer Maria R De Filippo Carey A Eberle Muzaffar Akram Nicola Fusco Shu Ichihara Rita A Sakr Yasushi Yatabe Anne Vincent‐Salomon Emad A Rakha Ian O Ellis Y Hannah Wen Britta Weigelt Stuart J Schnitt Jorge S Reis‐Filho |
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| Institution: | 1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA;2. Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, S?o Paulo, Brazil;3. Division of Pathology, Fondazione IRCCS Ca' Granda, Milan, Italy;4. Department of Pathology, Nagoya Medical Center, Nagoya, Japan;5. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA;6. Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan;7. Department of Biopathology, Institut Curie, Paris, France;8. Department of Pathology, Nottingham University, Nottingham, UK;9. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA |
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| Abstract: | Microglandular adenosis (MGA) is a rare proliferative lesion of the breast composed of small glands lacking myoepithelial cells and lined by S100‐positive, oestrogen receptor (ER)‐negative, progesterone receptor (PR)‐negative, and HER2‐negative epithelial cells. There is evidence to suggest that MGA may constitute a non‐obligate precursor of triple‐negative breast cancer (TNBC). We sought to define the genomic landscape of pure MGA and of MGA, atypical MGA (AMGA) and associated TNBCs, and to determine whether synchronous MGA, AMGA, and TNBCs would be clonally related. Two pure MGAs and eight cases of MGA and/or AMGA associated with in situ or invasive TNBC were collected, microdissected, and subjected to massively parallel sequencing targeting all coding regions of 236 genes recurrently mutated in breast cancer or related to DNA repair. Pure MGAs lacked clonal non‐synonymous somatic mutations and displayed limited copy number alterations (CNAs); conversely, all MGAs (n = 7) and AMGAs (n = 3) associated with TNBC harboured at least one somatic non‐synonymous mutation (range 3–14 and 1–10, respectively). In all cases where TNBCs were analyzed, identical TP53 mutations and similar patterns of gene CNAs were found in the MGA and/or AMGA and in the associated TNBC. In the MGA/AMGA associated with TNBC lacking TP53 mutations, somatic mutations affecting PI3K pathway‐related genes (eg PTEN, PIK3CA, and INPP4B) and tyrosine kinase receptor signalling‐related genes (eg ERBB3 and FGFR2) were identified. At diagnosis, MGAs associated with TNBC were found to display subclonal populations, and clonal shifts in the progression from MGA to AMGA and/or to TNBC were observed. Our results demonstrate the heterogeneity of MGAs, and that MGAs associated with TNBC, but not necessarily pure MGAs, are genetically advanced, clonal, and neoplastic lesions harbouring recurrent mutations in TP53 and/or other cancer genes, supporting the notion that a subset of MGAs and AMGAs may constitute non‐obligate precursors of TNBCs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
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| Keywords: | breast cancer precursor triple‐negative breast cancer TP53 targeted capture massively parallel sequencing mutations |
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