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Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer

  • Epidemiology
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Abstract

The aim of this study is to identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3–22.2, 3q27.1, 10q23.1, and 14q13.2–3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios. For bone metastasis, the hazard (95 % confidence interval) for the low-risk group was 0.32 (0.11–0.92) compared to the intermediate-risk group and 2.99 (1.74–5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17–0.66) and 2.33 (1.59–3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk.

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Acknowledgments

We thank Melissa May, Dr. Jeong Yun Shim, and Dr. Agbe Samuel for retrieving and processing all the tumor specimens used in the study; Wanda Williams, who supervised the medical record abstraction; Phyllis Adatto, who supervised the study staff; and Betsy C. Wertheim for careful review and editing of the manuscript. For providing tumor specimens and clinical data, the authors gratefully acknowledge for the MicMa cohort, Dr. Bjørn Naume, and Dr. Marit Synnestvedt; for the ULL cohort, Dr. Anita Langerød; for the MDG cohort, Dr. Vilde D. Haakensen and Dr. Åslaug Helland, all Oslo University Hospital, Norway. For the Uppsala cohort we wish to thank Dr. Johan Botling, Department of Surgery, Uppsala University, Sweden. For technical support performing the aCGH experiments we wish to thank Dr. Hans Kristian M. Vollan, Ida J. Schneider, and Eldri U. Due, Oslo University Hospital, Norway. This study was supported by the National Institutes of Health (NIH) through grant R01CA089608. Additional support was provided by Susan G. Komen for the Cure, by the National Breast Cancer Foundation, and by NIH through SPORE P50CA116199, MD Anderson’s Cancer Center Support Grant (CCSG) CA016672, and the Arizona Cancer Center’s CCSG CA023074. Grants to ALBD lab supporting this study: Norwegian Research Council grants 175240/S10, 159188/S10, and 193387/V50, Norwegian Cancer Society grant 138296-PR-2008-0108.

Conflict of interest

No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Yanhong Liu, Renke Zhou, Spyros Tsavachidis & Melissa L. Bondy

  2. Department of Genetics, Institute for Cancer Research, Oslo University Hospital and The Norwegian Radium Hospital, Oslo, Norway

    Lars O. Baumbusch, Jørgen Aarøe & Anne-Lise Børresen-Dale

  3. Departments of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Abenaa M. Brewster

  4. Departments of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kim-Anh Do

  5. Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Aysegul Sahin

  6. Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Gabriel N. Hortobagyi

  7. Departments of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Joseph H. Taube & Sendurai A. Mani

  8. Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, University of Oslo, Oslo, Norway

    Jørgen Aarøe & Anne-Lise Børresen-Dale

  9. Department of Surgery, Uppsala University, Uppsala, Sweden

    Fredrik Wärnberg

  10. Departments of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Gordon B. Mills

  11. Arizona Cancer Center, University of Arizona, 1515 N. Campbell Ave, Tucson, AZ, 85724, USA

    Patricia A. Thompson

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  1. Yanhong Liu
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  3. Lars O. Baumbusch
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Corresponding author

Correspondence to Patricia A. Thompson.

Additional information

Y. Liu and R. Zhou have contributed equally to this study.

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Liu, Y., Zhou, R., Baumbusch, L.O. et al. Genomic copy number imbalances associated with bone and non-bone metastasis of early-stage breast cancer. Breast Cancer Res Treat 143, 189–201 (2014). https://doi.org/10.1007/s10549-013-2796-3

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