Dataset Information

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

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.

SUBMITTER: Zhang L

PROVIDER: S-EPMC6178888 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Zhang Linfan L Feizi Nikta N Chi Chen C Hu Pingzhao P

Frontiers in genetics 20181001

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 ...[more]

PMID: 30337938

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Project description:Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

Project description:PurposeIt has been suggested that dysregulation of transcription factors expression or activity plays significant roles in breast cancer (BC) severity and poor prognosis. Therefore, our study aims to thoroughly evaluate the estrogen-related receptor isoforms (ESRRs) expression and copy number alteration (CNA) status and their association with clinicopathologic characteristics in BC.MethodsA METABRIC dataset consist of 2509 BC patients' samples was obtained from the cBioPortal public domain. The gene expression, putative CNA, and relevant tumor information of ESRRs were retrieved. ESRRs messenger RNA (mRNA) expression in BC cell lines was obtained from the Cancer Cell Line Encyclopedia (CCLE). Association and correlation analysis of ESRRs expression with BC clinicopathologic characteristics and molecular subtype were performed. Kaplan-Meier survival analysis was conducted to evaluate the prognostic value of ESRRs expression on patient survival.ResultsESRRα expression correlated negatively with patients' age and overall survival, whereas positively correlated with tumor size, the number of positive lymph nodes, and Nottingham prognostic index (NPI). Conversely, ESRRγ expression was positively correlated with patients' age and negatively correlated with NPI. ESRRα and ESRRγ expression were significantly associated with tumor grade, expression of hormone receptors, human epidermal growth factor receptor 2 (HER2), and molecular subtype, whereas ESRRβ was only associated with tumor stage. A significant and distinct association of each of ESRRs CNA with various clinicopathologic and prognostic factors was also observed. Kaplan-Meier survival analysis demonstrated no significant difference for survival curves among BC patients with high or low expression of ESRRα, β, or γ. On stratification, high ESRRα expression significantly reduced survival among premenopausal patients, patients with grade I/II, and early-stage disease. In BC cell lines, only ESRRα expression was significantly higher in HER2-positive cells. No significant association was observed between ESRRβ expression and any of the clinicopathologic characteristics examined.ConclusionsIn this clinical dataset, ESRRα and ESRRγ mRNA expression and CNA show a significant correlation and association with distinct clinicopathologic and prognostic parameters known to influence treatment outcomes; however, ESRRβ failed to show a robust role in BC pathogenesis. ESRRα and ESRRγ can be employed as therapeutic targets in BC-targeted therapy. However, the role of ESRRβ in BC pathogenesis remains unclear.

Dataset Information

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

Publications

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

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