title: The repertoire of somatic genetic alterations of acinic cell carcinomas of the breast: an exploratory, hypothesis-generating study.
abstract: Acinic cell carcinoma (ACC) of the breast is a rare form of triple-negative (that is, oestrogen receptor-negative, progesterone receptor-negative, HER2-negative) salivary gland-type tumour displaying serous acinar differentiation. Despite its triple-negative phenotype, breast ACCs are reported to have an indolent clinical behaviour. Here, we sought to define whether ACCs have a mutational repertoire distinct from that of other triple-negative breast cancers (TNBCs). DNA was extracted from microdissected formalin-fixed, paraffin-embedded sections of tumour and normal tissue from two pure and six mixed breast ACCs. Each tumour component of the mixed cases was microdissected separately. Tumour and normal samples were subjected to targeted capture massively parallel sequencing targeting all exons of 254 genes, including genes most frequently mutated in breast cancer and related to DNA repair. Selected somatic mutations were validated by targeted amplicon resequencing and Sanger sequencing. Akin to other forms of TNBC, the most frequently mutated gene found in breast ACCs was TP53 (one pure and six mixed cases). Additional somatic mutations affecting breast cancer-related genes found in ACCs included PIK3CA, MTOR, CTNNB1, BRCA1, ERBB4, ERBB3, INPP4B, and FGFR2. Copy number alteration analysis revealed complex patterns of gains and losses similar to those of common forms of TNBCs. Of the mixed cases analysed, identical somatic mutations were found in the acinic and the high-grade non-acinic components in two out of four cases analysed, providing evidence of their clonal relatedness. In conclusion, breast ACCs display the hallmark somatic genetic alterations found in high-grade forms of TNBC, including complex patterns of gene copy number alterations and recurrent TP53 mutations. Furthermore, we provide circumstantial genetic evidence to suggest that ACCs may constitute the substrate for the development of more aggressive forms of triple-negative disease.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|School of Pathology, University of Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Guerini-Rocco
authors.affiliation: Department of Pathology, University of Nottingham, Nottingham, UK.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Hodi
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, University of Nottingham, Nottingham, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
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.
authors.forename: Arnaud
authors.initials: A
authors.lastname: da Cruz Paula
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: Luciano G
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: De Mattos-Arruda
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Edelweiss
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.|School of Pathology, University of Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Fusco
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 Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.affiliation: Department of Pathology, University of Nottingham, 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: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D018267:Carcinoma, Acinar Cell / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D042282:Microdissection; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D010641:Phenotype; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: TP53; breast cancer; immunohistochemistry; massively parallel sequencing; triple-negative