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Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers.

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Głodzik, D 
Purdie, C 
Rye, IH 
Simpson, PT 
Staaf, J 


BACKGROUND: Complex clusters of rearrangements are a challenge in interpretation of cancer genomes. Some clusters of rearrangements demarcate clear amplifications of driver oncogenes but others are less well understood. A detailed analysis of rearrangements within these complex clusters could reveal new insights into selection and underlying mutational mechanisms. PATIENTS AND METHODS: 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. RESULTS: 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.



Adult, Age Distribution, Aged, Aged, 80 and over, Algorithms, Breast, Breast Neoplasms, Carrier Proteins, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 8, Cyclin D1, Datasets as Topic, Female, Gene Amplification, Genetic Loci, Genomics, Humans, Middle Aged, Oncogenes, Receptor, Fibroblast Growth Factor, Type 1, Translocation, Genetic, Whole Genome Sequencing

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Ann Oncol

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Elsevier BV
Cancer Research UK (23916)
Cancer Research UK (25274)
European Commission (242006)