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An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers

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Abstract

Breast cancer is a heterogeneous disease caused by the accumulation of genetic changes in neoplastic cells. We hypothesised that molecular subtypes of breast cancer may be driven by specific constellations of genes whose expression is regulated by gene copy number aberrations. To address this question, we analysed a series of 48 microdissected grade III ductal carcinomas using high resolution microarray comparative genomic hybridisation and mRNA expression arrays. There were 5,931 genes whose expression significantly correlates with copy number identified; out of these, 1,897 genes were significantly differentially expressed between basal-like, HER2 and luminal tumours. Ingenuity Pathway Analysis (IPA) revealed that ‘G1/S cell cycle regulation’ and ‘BRCA1 in DNA damage control’ pathways were significantly enriched for genes whose expression correlates with copy number and are differentially expressed between the molecular subtypes of breast cancer. IPA of genes whose expression significantly correlates with copy number in each molecular subtype individually revealed that canonical pathways involved in oestrogen receptor (ER) signalling and DNA repair are enriched for these genes. We also identified 32, 157 and 265 genes significantly overexpressed when amplified in basal-like, HER2 and luminal cancers, respectively. These lists include known and novel potential therapeutic targets (e.g. HER2 and PPM1D in HER2 cancers). Our results provide strong circumstantial evidence that different patterns of genetic aberrations in distinct molecular subtypes of breast cancer contribute to their specific transcriptomic profiles and that biological phenomena characteristic of each subtype (e.g. proliferation, HER2 and ER signalling) may be driven by specific patterns of copy number aberrations.

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Acknowledgments

This study was funded in part by Breakthrough Breast Cancer. B. Weigelt is supported by a Cancer Research UK Fellowship, J Palacios by RETICS: RD06/0020/0013 and PI 08/6080971 from Instituto de Salud Carlos III and P07-CVI-03100 from Consejería de Innovación Junta de Andalucía.

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Authors and Affiliations

  1. The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Rachael Natrajan, Alan Mackay, Felipe C. Geyer, David S. P. Tan, Christopher J. Lord, Radost Vatcheva, Alan Ashworth & Jorge S. Reis-Filho

  2. Cancer Research UK, London Research Institute, London, WC2A 3PX, UK

    Britta Weigelt

  3. Breakthrough Breast Research Unit, Guy’s Hospital, London, SE1 9RT, UK

    Anita Grigoriadis

  4. Paediatric Oncology, Institute of Cancer Research, Sutton, SM2 5NG, UK

    Chris Jones

  5. Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain

    Socorro M. Rodriguez-Pinilla

  6. Servicio de Anatomia Patologica, Hospital Virgen del Rocío, Seville, Spain

    Jose Palacios

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  1. Rachael Natrajan
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  2. Britta Weigelt
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  3. Alan Mackay
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  4. Felipe C. Geyer
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  5. Anita Grigoriadis
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  6. David S. P. Tan
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  7. Chris Jones
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  8. Christopher J. Lord
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  9. Radost Vatcheva
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  10. Socorro M. Rodriguez-Pinilla
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  11. Jose Palacios
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  12. Alan Ashworth
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  13. Jorge S. Reis-Filho
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Corresponding authors

Correspondence to Rachael Natrajan or Jorge S. Reis-Filho.

Additional information

Rachael Natrajan and Britta Weigelt contributed equally to the present study.

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Natrajan, R., Weigelt, B., Mackay, A. et al. An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers. Breast Cancer Res Treat 121, 575–589 (2010). https://doi.org/10.1007/s10549-009-0501-3

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