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Breast Cancer Research and Treatment

, Volume 143, Issue 1, pp 189–201 | Cite as

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

  • Yanhong Liu
  • Renke Zhou
  • Lars O. Baumbusch
  • Spyros Tsavachidis
  • Abenaa M. Brewster
  • Kim-Anh Do
  • Aysegul Sahin
  • Gabriel N. Hortobagyi
  • Joseph H. Taube
  • Sendurai A. Mani
  • Jørgen Aarøe
  • Fredrik Wärnberg
  • Anne-Lise Børresen-Dale
  • Gordon B. Mills
  • Patricia A. ThompsonEmail author
  • Melissa L. Bondy
Epidemiology

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.

Keywords

Breast cancer Bone metastasis Non-bone metastasis Copy number imbalances Molecular inversion probe array 

Notes

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.

Supplementary material

10549_2013_2796_MOESM1_ESM.docx (1.1 mb)
Supplementary material 1 (DOCX 1160 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Yanhong Liu
    • 1
  • Renke Zhou
    • 1
  • Lars O. Baumbusch
    • 2
  • Spyros Tsavachidis
    • 1
  • Abenaa M. Brewster
    • 3
  • Kim-Anh Do
    • 4
  • Aysegul Sahin
    • 5
  • Gabriel N. Hortobagyi
    • 6
  • Joseph H. Taube
    • 7
  • Sendurai A. Mani
    • 7
  • Jørgen Aarøe
    • 2
    • 8
  • Fredrik Wärnberg
    • 9
  • Anne-Lise Børresen-Dale
    • 2
    • 8
  • Gordon B. Mills
    • 10
  • Patricia A. Thompson
    • 11
    Email author
  • Melissa L. Bondy
    • 1
  1. 1.Department of Pediatrics, Dan L. Duncan Cancer CenterBaylor College of MedicineHoustonUSA
  2. 2.Department of Genetics, Institute for Cancer ResearchOslo University Hospital and The Norwegian Radium HospitalOsloNorway
  3. 3.Departments of Clinical Cancer PreventionThe University of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Departments of BiostatisticsThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.Departments of PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  6. 6.Departments of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  7. 7.Departments of Molecular PathologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  8. 8.Faculty of Medicine, K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical MedicineUniversity of OsloOsloNorway
  9. 9.Department of SurgeryUppsala UniversityUppsalaSweden
  10. 10.Departments of Systems BiologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  11. 11.Arizona Cancer CenterUniversity of ArizonaTucsonUSA

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