Abstract

Breast cancer is one of the most common cancers among women, and susceptibility is explained by genetic, lifestyle and environmental components. Copy Number Variants (CNVs) are structural DNA variations that contribute to diverse phenotypes via gene-dosage effects or cis-regulation. In this study, we aimed to identify germline CNVs associated with breast cancer susceptibility and their relevance to prognosis. We performed whole genome CNV genotyping in 422 cases and 348 controls using Human Affymetrix SNP 6 array. Principal component analysis for population stratification revealed 84 outliers leaving 366 cases and 320 controls of Caucasian ancestry for association analysis; CNVs with frequency > 10% and overlapping with protein coding genes were considered for breast cancer risk and prognostic relevance. Coding genes within the CNVs identified were interrogated for gene- dosage effects by correlating copy number status with gene expression profiles in breast tumor tissue. We identified 200 CNVs associated with breast cancer (q-value < 0.05). Of these, 21 CNV regions (overlapping with 22 genes) also showed association with prognosis. We validated representative CNVs overlapping with APOBEC3B and GSTM1 genes using the TaqMan assay. Germline CNVs conferred dosage effects on gene expression in breast tissue. The candidate CNVs identified in this study warrant independent replication.

Details

Title
Germline copy number variations are associated with breast cancer risk and prognosis
Author
Kumaran, Mahalakshmi 1 ; Cass, Carol E 2 ; Graham, Kathryn 2 ; Mackey, John R 2 ; Hubaux, Roland 3   VIAFID ORCID Logo  ; Lam, Wan 3 ; Yasui, Yutaka 4 ; Sambasivarao Damaraju 5 

1  Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada 
2  Department of Oncology, University of Alberta, Edmonton, Alberta, Canada 
3  Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada 
4  School of Public Health, University of Alberta, Edmonton, Alberta, Canada 
5  Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada; Cross Cancer Institute, Alberta Health Services, Edmonton, AB, Canada 
Pages
1-15
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-017-14799-7
ProQuest document ID
1961816230
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.