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Characterisation of amplification patterns and target genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours

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Abstract

Amplification of chromosomal region 11q13, containing the cell cycle regulatory gene CCND1, is frequently found in breast cancer and other malignancies. It is associated with the favourable oestrogen receptor (ER)-positive breast tumour phenotype, but also with poor prognosis and treatment failure. 11q13 spans almost 14 Mb and contains more than 200 genes and is affected by various patterns of copy number gains, suggesting complex mechanisms and selective pressure during tumour progression. In this study, we used 32 k tiling BAC array CGH to analyse 94 CCND1-amplified breast tumours from sporadic, hereditary, and familial breast cancers to fine map chromosome 11q13. A set containing 281 CCND1-non-amplified breast tumours was used for comparisons. We used gene expression data to further validate the functional effect of gene amplification. We identified six core regions covering 11q13.1-q14.1 that were amplified in different combinations. The major core contained CCND1, whereas two cores were found proximal of CCND1 and three distal. The majority of the CCND1-amplified tumours were ER-positive and classified as luminal B. Furthermore, we found that CCND1 amplification is associated with a more aggressive phenotype within histological grade 2 tumours and luminal A subtype tumours. Amplification was equally prevalent in familial and sporadic tumours, but strikingly rare in BRCA1- and BRCA2-mutated tumours. We conclude that 11q13 includes many potential target genes in addition to CCND1.

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Abbreviations

aCGH:

Array comparative genomic hybridisation

BFB:

Breakage-fusion-bridge

CCND1+:

CCND1-amplified tumours

CCND1−:

CCND1-non-amplified tumours

ER:

Oestrogen receptor

FGA:

Fraction of genome altered

FISH:

Fluorescence in situ hybridisation

GEO:

Gene expression omnibus

GEX:

Gene expression

GISTIC:

Genomic identification of significant targets in cancer

GOBO:

Gene expression-based outcome for breast cancer online

OS:

Overall survival

PR:

Progesterone receptor

SAT:

Sample adaptive threshold

SRO:

Smallest region of overlap

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Acknowledgments

This study was supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Berta Kamprad Foundation, the Gunnar Nilsson Foundation, the King Gustaf V Jubilee Foundation, the Knut & Alice Wallenberg Foundation, the Foundation for Strategic Research, and the IngaBritt and Arne Lundberg Foundation. The SCIBLU Genomics Centre is supported by governmental funding of clinical research within the national health services (ALF) and by Lund University.

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Oncology, Clinical Sciences, Lund University, 221 85, Lund, Sweden

    Karolina Holm, Johan Staaf, Göran Jönsson, Johan Vallon-Christersson, Cecilia Hegardt, Markus Ringnér & Åke Borg

  2. CREATE Health Strategic Centre for Translational Cancer Research, Lund University, BMC C13, 221 84, Lund, Sweden

    Karolina Holm, Johan Staaf, Göran Jönsson, Johan Vallon-Christersson, Markus Ringnér & Åke Borg

  3. Department of Pathology, Laboratory of Cell Biology, Landspitali University Hospital, 101, Reykjavik, Iceland

    Haukur Gunnarsson, Adalgeir Arason & Rosa B. Barkardottir

  4. Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland

    Adalgeir Arason & Rosa B. Barkardottir

  5. Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, 221 85, Lund, Sweden

    Linda Magnusson

  6. Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, BMC B10, 221 84, Lund, Sweden

    Åke Borg

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  1. Karolina Holm
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  2. Johan Staaf
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  3. Göran Jönsson
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Correspondence to Karolina Holm.

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Holm, K., Staaf, J., Jönsson, G. et al. Characterisation of amplification patterns and target genes at chromosome 11q13 in CCND1-amplified sporadic and familial breast tumours. Breast Cancer Res Treat 133, 583–594 (2012). https://doi.org/10.1007/s10549-011-1817-3

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