title: Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.
abstract: Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
authors.forename: Rachael
authors.initials: R
authors.lastname: Natrajan
authors.forename: Paul M
authors.initials: PM
authors.lastname: Wilkerson
authors.forename: Caterina
authors.initials: C
authors.lastname: Marchiò
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piscuoglio
authors.forename: Charlotte K Y
authors.initials: CK
authors.lastname: Ng
authors.forename: Patty
authors.initials: P
authors.lastname: Wai
authors.forename: Maryou B
authors.initials: MB
authors.lastname: Lambros
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Samartzis
authors.forename: Konstantin J
authors.initials: KJ
authors.lastname: Dedes
authors.forename: Jessica
authors.initials: J
authors.lastname: Frankum
authors.forename: Ilirjana
authors.initials: I
authors.lastname: Bajrami
authors.forename: Alicja
authors.initials: A
authors.lastname: Kopec
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay
authors.forename: Roger
authors.initials: R
authors.lastname: A'hern
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: Jarle
authors.initials: J
authors.lastname: Hakas
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: David
authors.initials: D
authors.lastname: Hardisson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Chandan
authors.initials: C
authors.lastname: Kumar-Sinha
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis-Filho
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D005260:Female; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D017423:Sequence Analysis, RNA; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: CDK12; PARP inhibitors; RNA sequencing; breast cancer; fusion transcripts; micropapillary; somatic mutation profiling