title: Genomic landscape of adenoid cystic carcinoma of the breast.
abstract: Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Luciano G
authors.identifier: http://orcid.org/0000-0002-9625-1183
authors.initials: LG
authors.lastname: Martelotto
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Maria R
authors.initials: MR
authors.lastname: De Filippo
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.affiliation: Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.affiliation: Department of Tumour Biology, Institut Curie, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fuhrmann
authors.affiliation: Department of Tumour Biology, Institut Curie, Paris, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Cyrta
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Huei-Chi
authors.initials: HC
authors.lastname: Wen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Lim
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Schultheis
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Y Hannah
authors.initials: YH
authors.lastname: Wen
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Edelweiss
authors.affiliation: Department of Tumour Biology, Institut Curie, Paris, France.
authors.forename: Odette
authors.initials: O
authors.lastname: Mariani
authors.affiliation: Sahlgrenska Cancer Center, Department of Pathology, University of Gothenburg, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.affiliation: Department of Surgical Oncology, Montpellier Cancer Institute (ICM), France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Colombo
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.affiliation: Department of Tumour Biology, Institut Curie, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Vincent-Salomon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D003528:Carcinoma, Adenoid Cystic / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020570:Genes, myb; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C545202:MYB-NFIB fusion protein, human; D015514:Oncogene Proteins, Fusion
keywords: MYB-NFIB; adenoid cystic carcinoma; genomics; massively parallel sequencing; triple-negative breast cancer