dc.contributor.author | Natrajan, R | |
dc.contributor.author | Wilkerson, PM | |
dc.contributor.author | Marchiò, C | |
dc.contributor.author | Piscuoglio, S | |
dc.contributor.author | Ng, CKY | |
dc.contributor.author | Wai, P | |
dc.contributor.author | Lambros, MB | |
dc.contributor.author | Samartzis, EP | |
dc.contributor.author | Dedes, KJ | |
dc.contributor.author | Frankum, J | |
dc.contributor.author | Bajrami, I | |
dc.contributor.author | Kopec, A | |
dc.contributor.author | Mackay, A | |
dc.contributor.author | A'hern, R | |
dc.contributor.author | Fenwick, K | |
dc.contributor.author | Kozarewa, I | |
dc.contributor.author | Hakas, J | |
dc.contributor.author | Mitsopoulos, C | |
dc.contributor.author | Hardisson, D | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Kumar-Sinha, C | |
dc.contributor.author | Ashworth, A | |
dc.contributor.author | Weigelt, B | |
dc.contributor.author | Sapino, A | |
dc.contributor.author | Chinnaiyan, AM | |
dc.contributor.author | Maher, CA | |
dc.contributor.author | Reis-Filho, JS | |
dc.date.accessioned | 2016-09-22T13:57:57Z | |
dc.date.issued | 2014-04-01 | |
dc.identifier.citation | The Journal of pathology, 2014, 232 (5), pp. 553 - 565 | |
dc.identifier.issn | 0022-3417 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/121 | |
dc.identifier.eissn | 1096-9896 | |
dc.identifier.doi | 10.1002/path.4325 | |
dc.description.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. | |
dc.format | Print-Electronic | |
dc.format.extent | 553 - 565 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Carcinoma, Papillary | |
dc.subject | Breast Neoplasms | |
dc.subject | Neoplasm Invasiveness | |
dc.subject | Genetic Predisposition to Disease | |
dc.subject | Oligonucleotide Array Sequence Analysis | |
dc.subject | Case-Control Studies | |
dc.subject | Gene Fusion | |
dc.subject | DNA Mutational Analysis | |
dc.subject | Sequence Analysis, RNA | |
dc.subject | Cell Proliferation | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Gene Dosage | |
dc.subject | Phenotype | |
dc.subject | Mutation | |
dc.subject | Time Factors | |
dc.subject | Female | |
dc.subject | Comparative Genomic Hybridization | |
dc.subject | DNA Copy Number Variations | |
dc.subject | Biomarkers, Tumor | |
dc.title | Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2013-12-29 | |
rioxxterms.funder | The Institute of Cancer Research | |
rioxxterms.identifier.project | Unspecified | |
rioxxterms.versionofrecord | 10.1002/path.4325 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2014-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of pathology | |
pubs.issue | 5 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Computational Biology and Chemogenomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.publication-status | Published | |
pubs.volume | 232 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Computational Biology and Chemogenomics | |
icr.researchteam | Clinical Trials & Statistics Unit | |
icr.researchteam | Functional Genomics | |
icr.researchteam | Gene Function | |
icr.researchteam | Glioma Team | |
dc.contributor.icrauthor | Natrajan, Rachael | |
dc.contributor.icrauthor | Mackay, Alan | |
dc.contributor.icrauthor | AHern, Roger | |
dc.contributor.icrauthor | Mitsopoulos, Konstantinos | |
dc.contributor.icrauthor | Lord, Christopher | |