한빛사논문
- 조회540
Jake June-Koo Lee1,2,3,*, Youngsook Lucy Jung1,4,14, Taek-Chin Cheong5,14, Jose Espejo Valle-Inclan6, Chong Chu1, Doga C. Gulhan1,2, Viktor Ljungström1, Hu Jin1, Vinayak V. Viswanadham1, Emma V. Watson7,8,9, Isidro Cortés-Ciriano6, Stephen J. Elledge2,7,9,10, Roberto Chiarle5,11, David Pellman2,10,12,13 & Peter J. Park1,2 ,*
1Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
2Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.
3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA.
5Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA.
6European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, UK.
7Department of Genetics, Harvard Medical School, Boston, MA, USA.
8Department of Systems Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
9Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA.
10Howard Hughes Medical Institute, Chevy Chase, MD, USA.
11Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
12Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
13Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
14These authors contributed equally: Youngsook Lucy Jung, Taek-Chin Cheong.
*Corresponding authors : Correspondence to Jake June-Koo Lee or Peter J. Park.
Abstract
Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure1-3 and the evolutionary trajectories4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism-which we term translocation-bridge amplification-involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage-fusion-bridge cycle prevalent in some and the translocation-bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.
논문정보
- Research article
- 2023년 05월 (BRIC 등록일 2023-06-14)
- 국외 연구진
- 의약학 > 종양의학
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