title: The genetic landscape of breast carcinomas with neuroendocrine differentiation.
abstract: Neuroendocrine breast carcinomas (NBCs) account for 2-5% of all invasive breast cancers, and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), and are HER2-negative and of luminal 'intrinsic' subtype. Here, we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER+/HER2-) breast carcinoma show distinct repertoires of somatic mutations. Eighteen ER+/HER2-NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissues were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast carcinomas and/or related to DNA repair. Their mutational repertoire was compared with that of ER+/HER2-breast carcinomas (n = 240), PAM50-defined luminal breast carcinomas (luminal A, n = 209; luminal B, n = 111) and invasive lobular carcinomas (n = 127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1-11) somatic mutations, similar to that of luminal B breast carcinomas (median = 3, range 0-17) but significantly higher than that of luminal A breast carcinomas (median = 3, range 0-18, p = 0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, and ARID1A (3/18, 17%), and PIK3CA, AKT1, and CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER+/HER2-, luminal A and invasive lobular carcinomas (p < 0.05), and showed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p < 0.05) and the transcription factor-encoding genes FOXA1 (17% versus 2%, p = 0.01) and TBX3 (17% versus 3%, p < 0.05) than common-type ER+/HER2-breast carcinomas. No TP53 somatic mutations were detected in NBCs. As compared with common forms of luminal breast carcinomas, NBCs show a distinctive repertoire of somatic mutations featuring lower frequencies of TP53 and PIK3CA mutations, enrichment for FOXA1 and TBX3 mutations, and, akin to neuroendocrine tumours from other sites, ARID1A mutations. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pathology, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, São Paulo, Brazil.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Geyer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Charlotte Ky
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: De Filippo
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cupo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Pathology Department, University Hospital, Cologne, Germany.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Burke
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Pathology Department, European Institute of Oncology, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini-Rocco
authors.affiliation: Department of Oncology, University of Turin, Turin, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology*; D018278:Carcinoma, Neuroendocrine / Q000473:pathology*; D058534:Class I Phosphatidylinositol 3-Kinases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: breast carcinoma; chromogranin A; copy number alterations; massively parallel sequencing; neuroendocrine differentiation; somatic mutations; synaptophysin