martes, 29 de enero de 2013

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

FULL-TEXT ►
PLOS ONE: Germline DNA Copy Number Aberrations Identified as Potential Prognostic Factors for Breast Cancer Recurrence

Research Article

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
    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.

No hay comentarios:

Publicar un comentario