Systems consequences of amplicon formation in human breast cancer
Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Cold Spring Harbor Laboratory Press
2014
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| Online Access: | http://hdl.handle.net/1721.1/90963 |
| _version_ | 1826216731719237632 |
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| author | Inaki, Koichiro Menghi, Francesca Woo, Xing Yi Wagner, Joel Patrick Jacques, Pierre-Étienne Lee, Yi Fang Shreckengast, Phung Trang Soon, Wendy WeiJia Malhotra, Ankit Teo, Audrey S.M. Hillmer, Axel M. Khng, Alexis Jiaying Ruan, Xiaoan Ong, Swee Hoe Bertrand, Denis Nagarajan, Niranjan Karuturi, R. Krishna Murthy Miranda, Alfredo Hidalgo Liu, Edison T. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Inaki, Koichiro Menghi, Francesca Woo, Xing Yi Wagner, Joel Patrick Jacques, Pierre-Étienne Lee, Yi Fang Shreckengast, Phung Trang Soon, Wendy WeiJia Malhotra, Ankit Teo, Audrey S.M. Hillmer, Axel M. Khng, Alexis Jiaying Ruan, Xiaoan Ong, Swee Hoe Bertrand, Denis Nagarajan, Niranjan Karuturi, R. Krishna Murthy Miranda, Alfredo Hidalgo Liu, Edison T. |
| author_sort | Inaki, Koichiro |
| collection | MIT |
| description | Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer. |
| first_indexed | 2024-09-23T16:52:12Z |
| format | Article |
| id | mit-1721.1/90963 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:52:12Z |
| publishDate | 2014 |
| publisher | Cold Spring Harbor Laboratory Press |
| record_format | dspace |
| spelling | mit-1721.1/909632022-09-29T22:02:46Z Systems consequences of amplicon formation in human breast cancer Inaki, Koichiro Menghi, Francesca Woo, Xing Yi Wagner, Joel Patrick Jacques, Pierre-Étienne Lee, Yi Fang Shreckengast, Phung Trang Soon, Wendy WeiJia Malhotra, Ankit Teo, Audrey S.M. Hillmer, Axel M. Khng, Alexis Jiaying Ruan, Xiaoan Ong, Swee Hoe Bertrand, Denis Nagarajan, Niranjan Karuturi, R. Krishna Murthy Miranda, Alfredo Hidalgo Liu, Edison T. Massachusetts Institute of Technology. Department of Biological Engineering Wagner, Joel Patrick Chromosomal structural variations play an important role in determining the transcriptional landscape of human breast cancers. To assess the nature of these structural variations, we analyzed eight breast tumor samples with a focus on regions of gene amplification using mate-pair sequencing of long-insert genomic DNA with matched transcriptome profiling. We found that tandem duplications appear to be early events in tumor evolution, especially in the genesis of amplicons. In a detailed reconstruction of events on chromosome 17, we found large unpaired inversions and deletions connect a tandemly duplicated ERBB2 with neighboring 17q21.3 amplicons while simultaneously deleting the intervening BRCA1 tumor suppressor locus. This series of events appeared to be unusually common when examined in larger genomic data sets of breast cancers albeit using approaches with lesser resolution. Using siRNAs in breast cancer cell lines, we showed that the 17q21.3 amplicon harbored a significant number of weak oncogenes that appeared consistently coamplified in primary tumors. Down-regulation of BRCA1 expression augmented the cell proliferation in ERBB2-transfected human normal mammary epithelial cells. Coamplification of other functionally tested oncogenic elements in other breast tumors examined, such as RIPK2 and MYC on chromosome 8, also parallel these findings. Our analyses suggest that structural variations efficiently orchestrate the gain and loss of cancer gene cassettes that engage many oncogenic pathways simultaneously and that such oncogenic cassettes are favored during the evolution of a cancer. Singapore. Agency for Science, Technology and Research National Science Foundation (U.S.) (East Asia and Pacific Summer Institutes (OISE-1108282)) 2014-10-17T14:38:49Z 2014-10-17T14:38:49Z 2014-09 Article http://purl.org/eprint/type/JournalArticle 1088-9051 http://hdl.handle.net/1721.1/90963 Inaki, K., F. Menghi, X. Y. Woo, J. P. Wagner, P.-E. Jacques, Y. F. Lee, P. T. Shreckengast, et al. “Systems Consequences of Amplicon Formation in Human Breast Cancer.” Genome Research 24, no. 10 (September 3, 2014): 1559–1571. en_US http://dx.doi.org/10.1101/gr.164871.113 Genome Research Creative Commons Attribution http://creativecommons.org/licenses/by-nc/4.0/ application/pdf Cold Spring Harbor Laboratory Press Cold Spring Harbor Laboratory Press |
| spellingShingle | Inaki, Koichiro Menghi, Francesca Woo, Xing Yi Wagner, Joel Patrick Jacques, Pierre-Étienne Lee, Yi Fang Shreckengast, Phung Trang Soon, Wendy WeiJia Malhotra, Ankit Teo, Audrey S.M. Hillmer, Axel M. Khng, Alexis Jiaying Ruan, Xiaoan Ong, Swee Hoe Bertrand, Denis Nagarajan, Niranjan Karuturi, R. Krishna Murthy Miranda, Alfredo Hidalgo Liu, Edison T. Systems consequences of amplicon formation in human breast cancer |
| title | Systems consequences of amplicon formation in human breast cancer |
| title_full | Systems consequences of amplicon formation in human breast cancer |
| title_fullStr | Systems consequences of amplicon formation in human breast cancer |
| title_full_unstemmed | Systems consequences of amplicon formation in human breast cancer |
| title_short | Systems consequences of amplicon formation in human breast cancer |
| title_sort | systems consequences of amplicon formation in human breast cancer |
| url | http://hdl.handle.net/1721.1/90963 |
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