title: Microglandular adenosis associated with triple-negative breast cancer is a neoplastic lesion of triple-negative phenotype harbouring TP53 somatic mutations.
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.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Department of Pathology, European Institute of Oncology, Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini-Rocco
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: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
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: Maria R
authors.initials: MR
authors.lastname: De Filippo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Carey A
authors.initials: CA
authors.lastname: Eberle
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Muzaffar
authors.initials: M
authors.lastname: Akram
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Division of Pathology, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fusco
authors.affiliation: Department of Pathology, Nagoya Medical Center, Nagoya, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Ichihara
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Department of Biopathology, Institut Curie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Pathology, Nottingham University, Nottingham, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Pathology, Nottingham University, Nottingham, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Y Hannah
authors.initials: YH
authors.lastname: Wen
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, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
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: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002277:Carcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005348:Fibrocystic Breast Disease / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011230:Precancerous Conditions / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D012189:Retrospective Studies; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53; breast cancer precursor; mutations; targeted capture massively parallel sequencing; triple-negative breast cancer