Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers
Publication year
2018Source
Annals of Oncology, 29, 11, (2018), pp. 2223-2231ISSN
Publication type
Article / Letter to editor
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Organization
Radiation Oncology
Laboratory Medicine
Journal title
Annals of Oncology
Volume
vol. 29
Issue
iss. 11
Page start
p. 2223
Page end
p. 2231
Subject
Radboudumc 17: Women's cancers RIMLS: Radboud Institute for Molecular Life Sciences; Radiation Oncology - Radboud University Medical CenterAbstract
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.
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- Academic publications [245050]
- Electronic publications [132309]
- Faculty of Medical Sciences [93209]
- Open Access publications [105922]
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