Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers.
Annals of oncology : official journal of the European Society for Medical Oncology
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Głodzik, D., Purdie, C., Rye, I., Simpson, P., Staaf, J., Span, P., Russnes, H., & et al. (2018). Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers.. Annals of oncology : official journal of the European Society for Medical Oncology, 29 (11), 2223-2231. https://doi.org/10.1093/annonc/mdy404
Background Complex clusters of rearrangements in cancer genomes are a challenge to interpret. Some are clear amplifications of driver oncogenes but others are less well understood. Detailed analysis of rearrangements within these complex clusters could reveal new insights into selection, and underlying mutational mechanisms. Results Here, we systematically investigate rearrangements that are densely clustered in individual tumours in a cohort of 560 breast cancers. Applying an agnostic approach, we identify 21 hotspots where clustered rearrangements recur across cancers. Some hotspots coincide with known oncogene loci including CCND1, ERBB2, ZNF217, chr8:ZNF703/FGFR1, IGF1R, and MYC. Others contain cancer genes not typically associated with breast cancer: MCL1, PTP4A1 and MYB. Intriguingly, we identify clustered rearrangements that physically connect distant hotspots. In particular, we observe simultaneous amplification of chr8:ZNF703/FGFR1 and chr11:CCND1 where deep analysis reveals that a chr8-chr11 translocation is likely to be an early, critical, initiating event. Conclusions We present an overview of complex rearrangements in breast cancer, highlighting a potential new way for detecting drivers and revealing novel mechanistic insights into the formation of two common amplicons.
Breast, Chromosomes, Human, Pair 8, Chromosomes, Human, Pair 11, Humans, Breast Neoplasms, Translocation, Genetic, Cyclin D1, Carrier Proteins, Genomics, Age Distribution, Gene Amplification, Oncogenes, Algorithms, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Receptor, Fibroblast Growth Factor, Type 1, Genetic Loci, Datasets as Topic, Whole Genome Sequencing
Cancer Research UK (23916)
Cancer Research UK (25274)
EC FP7 CP (242006)
External DOI: https://doi.org/10.1093/annonc/mdy404
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285358
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/