Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines Export

@article{citeulike:2501642, abstract = {HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.}, author = {Arriola, Edurne and Marchio, Caterina and Tan, David S. P. and Drury, Suzanne C. and Lambros, Maryou B. and Natrajan, Rachael and Rodriguez-Pinilla, Socorro M. and Mackay, Alan and Tamber, Narinder and Fenwick, Kerry and Jones, Chris and Dowsett, Mitch and Ashworth, Alan and Reis-Filho, Jorge S.}, citeulike-article-id = {2501642}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/labinvest.2008.19}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18332872}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18332872}, comment = {The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets.}, doi = {10.1038/labinvest.2008.19}, issn = {0023-6837}, journal = {Laboratory Investigation}, keywords = {17q12, aggressiveness, breast, cancer, gene-expression, her2, molecular, thelist, top2a}, number = {current}, posted-at = {2009-04-27 13:43:21}, priority = {2}, publisher = {Nature Publishing Group}, title = {Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines}, url = {http://dx.doi.org/10.1038/labinvest.2008.19}, volume = {aop} }

TY - JOUR ID - citeulike:2501642 L3 - citeulike-article-id:2501642 N2 - HER2 and TOP2A are targets for the therapeutic agents trastuzumab and anthracyclines and are frequently amplified in breast cancers. The aims of this study were to provide a detailed molecular genetic analysis of the 17q12-q21 amplicon in breast cancers harbouring HER2/TOP2A co-amplification and to investigate additional recurrent co-amplifications in HER2/TOP2A-co-amplified cancers. In total, 15 breast cancers with HER2 amplification, 10 of which also harboured TOP2A amplification, as defined by chromogenic in situ hybridisation, and 6 breast cancer cell lines known to be amplified for HER2 were subjected to high-resolution microarray-based comparative genomic hybridisation analysis. This revealed that the genomes of 12 cases were characterised by at least one localised region of clustered, relatively narrow peaks of amplification, with each cluster confined to a single chromosome arm (ie 'firestorm' pattern) and 3 cases displayed many narrow segments of duplication and deletion affecting the vast majority of chromosomes (ie 'sawtooth' pattern). The smallest region of amplification (SRA) on 17q12 in the whole series extended from 34.73 to 35.48 Mb, and encompassed HER2 but not TOP2A. In HER2/TOP2A-co-amplified samples, the SRA extended from 34.73 to 36.54 Mb, spanning a region of approximately 1.8 Mb. Apart from HER2 and TOP2A, this region encompassed four additional genes whose expression levels as defined by quantitative real-time PCR are significantly higher in HER2/TOP2A-co-amplified vs HER2-amplified breast cancers: CASC3, CDC6, RARA and SMARCE1. Of the cell lines studied, SKBR3 and UACC812 showed HER2/TOP2A co-amplification. In conclusion, this is the first detailed genome-wide characterisation of HER2/TOP2A-amplified breast cancers; cell lines were identified that can be used to model these cancers in vitro. The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets. IS - current JF - Laboratory Investigation SN - 0023-6837 TI - Genomic analysis of the HER2/TOP2A amplicon in breast cancer and breast cancer cell lines PB - Nature Publishing Group VL - aop KW - 17q12 KW - aggressiveness KW - breast KW - cancer KW - gene-expression KW - her2 KW - molecular KW - thelist KW - top2a N1 - The 17q12 amplicon is complex and harbours multiple genes that may be associated with breast cancer development and progression, and potentially exploitable as therapeutic targets. AU - Arriola, Edurne AU - Marchio, Caterina AU - Tan, David AU - Drury, Suzanne AU - Lambros, Maryou AU - Natrajan, Rachael AU - Rodriguez-Pinilla, Socorro AU - Mackay, Alan AU - Tamber, Narinder AU - Fenwick, Kerry AU - Jones, Chris AU - Dowsett, Mitch AU - Ashworth, Alan AU - Reis-Filho, Jorge UR - http://dx.doi.org/10.1038/labinvest.2008.19 ER -