TY - JOUR
T1 - Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast
AU - Natrajan, Rachael
AU - Wilkerson, Paul M.
AU - Marchiò, Caterina
AU - Piscuoglio, Salvatore
AU - Ng, Charlotte K Y
AU - Wai, Patty
AU - Lambros, Maryou B.
AU - Samartzis, Eleftherios P.
AU - Dedes, Konstantin J.
AU - Frankum, Jessica
AU - Bajrami, Ilirjana
AU - Kopec, Alicja
AU - Mackay, Alan
AU - A'Hern, Roger
AU - Fenwick, Kerry
AU - Kozarewa, Iwanka
AU - Hakas, Jarle
AU - Mitsopoulos, Costas
AU - Hardisson, David
AU - Lord, Christopher J.
AU - Kumar-Sinha, Chandan
AU - Ashworth, Alan
AU - Weigelt, Britta
AU - Sapino, Anna
AU - Chinnaiyan, Arul M.
AU - Maher, Christopher A.
AU - Reis-Filho, Jorge S.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - breast cancer
KW - CDK12
KW - fusion transcripts
KW - micropapillary
KW - PARP inhibitors
KW - RNA sequencing
KW - somatic mutation profiling
UR - http://www.scopus.com/inward/record.url?scp=84895929400&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84895929400&partnerID=8YFLogxK
U2 - 10.1002/path.4325
DO - 10.1002/path.4325
M3 - Article
C2 - 24395524
AN - SCOPUS:84895929400
VL - 232
SP - 553
EP - 565
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 5
ER -