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

Glodzik, Dominik LU ; Purdie, Colin A; Rye, Inga Hansine; Simpson, Peter T; Staaf, Johan LU ; Span, Paul N.; Russnes, Hege and Nik-Zainal, Serena (2018) In Annals of Oncology
Abstract
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,... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Annals of Oncology
publisher
Oxford University Press
external identifiers
  • scopus:85058602269
ISSN
1569-8041
DOI
10.1093/annonc/mdy404
language
English
LU publication?
yes
id
10d1361a-bb75-41a1-aa49-912cca208899
date added to LUP
2018-11-23 13:24:53
date last changed
2019-02-17 05:06:40
@article{10d1361a-bb75-41a1-aa49-912cca208899,
  abstract     = {Background<br/><br/>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.<br/>Patients and methods<br/><br/>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.<br/>Results<br/><br/>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.<br/>Conclusions<br/><br/>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.},
  articleno    = {30252041},
  author       = {Glodzik, Dominik and Purdie, Colin A and Rye, Inga Hansine and Simpson, Peter T and Staaf, Johan and Span, Paul N. and Russnes, Hege and Nik-Zainal, Serena},
  issn         = {1569-8041},
  language     = {eng},
  month        = {09},
  publisher    = {Oxford University Press},
  series       = {Annals of Oncology},
  title        = {Mutational mechanisms of amplifications revealed by analysis of clustered rearrangements in breast cancers},
  url          = {http://dx.doi.org/10.1093/annonc/mdy404},
  year         = {2018},
}