Association Analysis of Somatic Copy Number Alteration Burden With Breast Cancer Survival.

Linfan Zhang,Nikta Feizi,Chen Chi,Pingzhao Hu

doi:10.3389/fgene.2018.00421

Linfan Zhang, Nikta Feizi + Show 2 more

Open Access

https://doi.org/10.3389/fgene.2018.00421

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Abstract

The increasing prevalence of diagnosed breast cancer cases emphasizes the urgent demand for developing new prognostic breast cancer biomarkers. Copy number alteration (CNA) burden measured as the percentage of the genome affected by CNAs has emerged as a potential candidate to this aim. Using somatic CNA data obtained from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium), we implemented Kaplan-Meier estimators and Cox proportional hazards models to examine the association of CNA burden with patient’s overall survival (OS) and disease specific survival (DSS). We also evaluated the association by considering patients’ age and tumor subtypes using stratified Cox models. We delineated the distribution of CNA burden in sample genomes and highlighted chromosomes 1, 8, and 16 as the carriers of the highest CNA burden. We identified a strong association between CNA burden and age as well as CNA burden and breast cancer PAM50 subtypes. We found that controlling the effects of both age (bound by 45-year) and PAM50 subtypes on patient survival using stratified Cox models, would still result in significant association between CNA burden and patients overall survival in both Discovery and Validation data. The same trend was observed in disease specific survival when only PAM50 subtypes were controlled in the stratified Cox models. Our analysis showed that there is a significant association between CNA burden and breast cancer survival. This result is also validated by using TCGA (The Cancer Genome Atlas) data. CNA burden of breast cancer patients has a considerable potential to be used as a novel prognostic biomarker.

Highlights

With a global estimate of 1.7 million newly diagnosed cases, breast cancer continues to be the most common malignancy affecting women worldwide
We showed an association between PAM50 subtypes and Copy number alteration (CNA) burden, as the incidence of Luminal B tumors increases with CNA burden while the incidence of Normal-like tumors decreases
We reported a relationship between age and CNA burden since older people tend to have higher CNA burden

Summary

Introduction

With a global estimate of 1.7 million newly diagnosed cases, breast cancer continues to be the most common malignancy affecting women worldwide. Being highly influenced by mutations in oncogenes such as ErbB2 and tumor suppressors such as TP53 and BRCA1/2, breast tumors are mainly governed by amplifications, deletions or rearrangements of chromosomal segments (i.e., copy number alterations, CNAs) rather than mutations in a single gene (Ciriello et al, 2013). Accumulated somatic mutations such as CNAs, single nucleotide substitutions, and translocations appear to have an important role in determining cancer progression (Futreal et al, 2004). CNAs identified in breast cancer patients could be regarded as potential biomarkers providing a considerable opportunity for therapeutic interventions (Stuart and Sellers, 2009)

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