Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers
Open accessAbstract
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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The complex rearrangements were associated with oncogene amplification and showed evidence of BFB and chromothripsis as a potential tumorigenesis mechanism.
“The complex rearrangements were associated with amplification of various oncogenes and showed evidence of BFB and chromothripsis as a potential mechanism driving tumorigenesis [18].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [18]
Telomeric erosion causing dicentric chromosome formation could lead to BFB and/or chromothripsis.
“raising the possibility that dicentric chromosome formation due to telomeric erosion could lead to BFB and/or chromothripsis [17, 18].”
From Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers (2019) · cites this paper as [18]
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“We observed that ‘non-BRCA1/2-like’ tumours had shorter telomeres than BRCAdeficient tumours (supplementary Figure S11, available at Annals of Oncology online) raising the possibility that dicentric chromosome formation due to telomeric erosion could lead to BFB and/ or chromothripsis [17, 18].”
BackgroundSelf-citation
- Authors
- Głodzik, D., Purdie, C., Rye, I. H., Simpson, P. T., Staaf, J., Span, P. N., Russnes, H. G., & Nik-Zainal, S.
- Affiliations
- Lund University (SE)
- Ninewells Hospital (GB)
- Oslo University Hospital (NO)
- The University of Queensland (AU)
- Radboud University Medical Center (NL)
- Venue
- Annals of Oncology
- Publisher
- Elsevier BV
- Published
- 2018-11
- Volume
- 29
- Issue
- 11
- Pages
- 2223-2231
- ISSN
- 0923-7534 (ISSN-L)
- PMC
- PMC6290883
- OpenAlex
- W2892516835
- Cited by
- 45
- References
- 15
- Citations by year
- 2026: 3 · 2025: 1 · 2023: 2 · 2022: 11 · 2021: 6 · 2020: 15 · 2019: 6
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
- Lund University Publications (Lund University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Apollo (cc-by)
- Funders
- Breast Cancer Somatic Genetics Study
- BASIS
- European Community's Seventh Framework Programme (FP7/2010-2014, 242006)
- Wellcome Trust (077012/Z/05/Z)
- Institut National du Cancer France (226-2009, 02-2011, 41-2012, 144-2008, 06-2012)
- Korean Health Technology R&D Project
- Ministry of Health & Welfare (A111218-SC01)
- Wellcome Trust Strategic Award (101126/B/13/Z, EU-FP7-)
- SUPPRESSTEM
- Lund University
- CRUK
- Advanced Clinician Scientist Award (C60100/A23916)
- IHR
- HGR
- Health Region South-East, Norway
- Norwegian Cancer Society
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
- Keywords
- breast cancer, gene amplification, mutational mechanisms, CCND1, ERBB2, ZNF217, IGF-1 receptor, c-Myc, Mcl-1, PTP4A1, MYB, chromosomal translocation, driver genes
- MeSH terms
- Whole Genome Sequencing, Adult, Aged, Aged, 80 and over, Algorithms, Breast, Breast Neoplasms, Carrier Proteins, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 8, Female, Gene Amplification, Humans, Middle Aged, Oncogenes, Translocation, Genetic, Age Distribution, Cyclin D1, Genomics, Receptor, Fibroblast Growth Factor, Type 1, Genetic Loci, Datasets as Topic
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