Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence

Yadav Sapkota,
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
X
Sunita Ghosh,
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
X
Raymond Lai,
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
X
Bradley P. Coe,
Affiliation: Department of Genome Sciences, University of Washington, School of Medicine, Seattle, Washington, United States of America
X
Carol E. Cass,
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
X
Yutaka Yasui,
Affiliation: Department of Public Health Sciences, University of Alberta, Edmonton, Alberta, Canada
X
John R. Mackey,
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
X
Sambasivarao Damaraju mail
* E-mail: Sambasivarao.Damaraju@albertahealthservices.ca
Affiliations: Cross Cancer Institute, Alberta Health Services, Edmonton, Alberta, Canada, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
X

Hide Figures

Abstract

Breast cancer recurrence (BCR) is a common treatment outcome despite curative-intent primary treatment of non-metastatic breast cancer. Currently used prognostic and predictive factors utilize tumor-based markers, and are not optimal determinants of risk of BCR. Germline-based copy number aberrations (CNAs) have not been evaluated as determinants of predisposition to experience BCR. In this study, we accessed germline DNA from 369 female breast cancer subjects who received curative-intent primary treatment following diagnosis. Of these, 155 experienced BCR and 214 did not, after a median duration of follow up after breast cancer diagnosis of 6.35 years (range = 0.60–21.78) and 8.60 years (range = 3.08–13.57), respectively. Whole genome CNA genotyping was performed on the Affymetrix SNP array 6.0 platform. CNAs were identified using the SNP-Fast Adaptive States Segmentation Technique 2 algorithm implemented in Nexus Copy Number 6.0. Six samples were removed due to poor quality scores, leaving 363 samples for further analysis. We identified 18,561 CNAs with ≥1 kb as a predefined cut-off for observed aberrations. Univariate survival analyses (log-rank tests) identified seven CNAs (two copy number gains and five copy neutral-loss of heterozygosities, CN-LOHs) showing significant differences (P<2 .01="">−5

) in recurrence-free survival (RFS) probabilities with and without CNAs.We also observed three additional but distinct CN-LOHs showing significant differences in RFS probabilities (P<2 .86="">−5) when analyses were restricted to stratified cases (luminal A, n = 208) only. After adjusting for tumor stage and grade in multivariate analyses (Cox proportional hazards models), all the CNAs remained strongly associated with the phenotype of BCR. Of these, we confirmed three CNAs at 17q11.2, 11q13.1 and 6q24.1 in representative samples using independent genotyping platforms. Our results suggest further investigations on the potential use of germline DNA variations as prognostic markers in cancer-associated phenotypes.

Citation: Sapkota Y, Ghosh S, Lai R, Coe BP, Cass CE, et al. (2013) Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence. PLoS ONE 8(1): e53850. doi:10.1371/journal.pone.0053850
Editor: Qing-Yi Wei, The University of Texas MD Anderson Cancer Center, United States of America

Received: August 6, 2012; Accepted: December 5, 2012; Published: January 16, 2013
Copyright: © 2013 Sapkota et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors would like to acknowledge Alberta Cancer Foundation, Alberta Cancer Prevention and Legacy Fund, managed by Alberta Innovates-Health Solutions and CBCF-Prairies/NWT Region for funding support to the CBCF Tumor Bank. Funding for this project was provided by Alberta Cancer Research Institute (ACRI), CBCF operating grants and Alberta Cancer Board (ACB) operating grants to SD. BPC is supported by a post-doctoral fellowship from Canadian Institute of Health Research, Canada. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: Sambasivarao.Damaraju@albertahealthservices.ca