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Subtypes of familial breast tumours revealed by expression and copy number profiling

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Abstract

Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumours by gene expression profiling and found that 74% BRCA1 tumours were basal-like, 73% of BRCA2 tumours were luminal A or B, and 52% non-BRCA1/2 tumours were luminal A. Thirty-four tumours were also analysed by single nucleotide polymorphism–comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumour was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumours were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumours (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumour suppressor genes were also detected, including in basal tumours (5q and 9p), and basal and luminal tumours (10q). This study highlights the heterogeneity of familial tumours and the clinical consequences for treatment and prognosis.

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Acknowledgements

We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contributed to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. GCT and KKK are NHMRC Research Fellows. CE holds the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic, is a Doris Duke Distinguished Clinical Scientist and an American Cancer Society Clinical Research Professor. We also wish to thank Jelle Wesseling, pathologist, and Petra Kristel, technician, for helping with the selection of BRCA2 tumours from the Netherlands Cancer Institute. This study was supported by grants from the National Breast Cancer Foundation and the NHMRC.

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Authors and Affiliations

  1. Queensland Institute of Medical Research, Brisbane, Australia

    Nic Waddell, Jeremy Arnold, Sibylle Cocciardi, Anna Marsh, Joan Riley, Cameron N. Johnstone, Kumkum Khanna & Georgia Chenevix-Trench

  2. Molecular & Cellular Pathology, School of Medicine and The University of Queensland Centre for Clinical Research, Brisbane, Australia

    Leonard da Silva, Lynne Reid, Patricia Keith, Peter T. Simpson & Sunil R. Lakhani

  3. MRC Toxicology Unit, Leicester, UK

    Joan Riley

  4. Peter MacCallum Cancer Centre, Melbourne, Australia

    Cameron N. Johnstone, Max Yan & Stephen Fox

  5. Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Mohammed Orloff, Guillaume Assie & Charis Eng

  6. Departments of Pathology and Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    Peter Devilee

  7. Department of Medical Oncology, Fox Chase Cancer Center, Women’s Cancer Program, Philadelphia, PA, USA

    Andrew K. Godwin

  8. DNA-Diagnostic Laboratory of the Family Cancer Clinic, Department of Pathology, Antoni Van Leeuwenhoek Hospital, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Frans B.L. Hogervorst

  9. Mayo Clinic College of Medicine, Rochester, MN, USA

    Fergus Couch

  10. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, Brisbane, Australia

    Sean Grimmond

  11. UCL Cancer Institute, London, UK

    James M. Flanagan

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  1. Nic Waddell
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Correspondence to Georgia Chenevix-Trench.

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Waddell, N., Arnold, J., Cocciardi, S. et al. Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res Treat 123, 661–677 (2010). https://doi.org/10.1007/s10549-009-0653-1

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