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<2.01×10−5) 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<2.86×10−5) 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.
Highlights
Breast cancer is the most common epithelial malignancy among women in the developed world, with more than 200,000 new cases and 39,000 deaths estimated in the United States in 2012 [1]; comparable statistics were observed in Canada in 2011 [2]
We observed three copy number gains that were present in all 363 samples
9,123 of the copy number aberrations (CNAs) identified in our 363 samples exhibited either complete (100%) or partial overlap with known germline copy number variations (CNVs) reported in the Database of Genomic Variants (DGV), Toronto
Summary
Breast cancer is the most common epithelial malignancy among women in the developed world, with more than 200,000 new cases and 39,000 deaths estimated in the United States in 2012 [1]; comparable statistics were observed in Canada in 2011 [2]. During the years 1998–2008, cancer related death rates have decreased by more than 1% per year in North American women and breast cancer explains one-third of this total decline [1]. Standard guideline-based therapy for non-metastatic breast cancer typically includes surgical excision of localized tumor and involved lymph nodes, followed by adjuvant systemic and radiotherapies to eradicate any residual micro-metastatic deposits. Both systemic chemotherapy and adjuvant endocrine therapy have reduced breast cancer recurrence and death [3]. Clinicopathological characteristics of tumors remain imperfect prognostic classifiers, in part due to the molecular heterogeneity of breast cancer
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