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

Glodzik, DominikLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Forskningsgrupp Lungcancer,Forskargrupper vid Lunds universitet,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Research Group Lung Cancer,Lund University Research Groups,Wellcome Trust Sanger Institute (författare)

BackgroundComplex 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 methodsHere, 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.ResultsSome 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.ConclusionsWe 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.

Purdie, Colin AUniversity of Dundee (författare)
Rye, Inga HansineNorwegian Radium Hospital,University of Oslo (författare)
Simpson, Peter TUniversity of Queensland (författare)
Staaf, JohanLund University,Lunds universitet,Bröstcancer-genetik,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breastcancer-genetics,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)onk-jst (författare)
Span, Paul N.Royal Brisbane and Women's Hospital,University of Queensland (författare)
Russnes, HegeNorwegian Radium Hospital,University of Oslo (författare)
Nik-Zainal, SerenaWellcome Trust Sanger Institute (författare)
Bröstcancer-genetikSektion I (creator_code:org_t)

Av författaren/redakt...: Glodzik, Dominik; Purdie, Colin A; Rye, Inga Hansin ...; Simpson, Peter T; Staaf, Johan; Span, Paul N.; visa fler...; Russnes, Hege; Nik-Zainal, Sere ...; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Cancer och onkol ...

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