Dataset Information

Comprehensive identification and characterization of somatic copy number alterations in triple?negative breast cancer.

ABSTRACT: Triple?negative breast cancer (TNBC) accounts for ~15% of all breast cancer diagnoses each year. Patients with TNBC tend to have a higher risk for early relapse and a worse prognosis. TNBC is characterized by extensive somatic copy number alterations (CNAs). However, the DNA CNA profile of TNBC remains to be extensively investigated. The present study assessed the genomic profile of CNAs in 201 TNBC samples, aiming to identify recurrent CNAs that may drive the pathogenesis of TNBC. In total, 123 regions of significant amplification and deletion were detected using the Genomic Identification of Significant Targets in Cancer algorithm, and potential driver genes for TNBC were identified. A total of 31 samples exhibited signs of chromothripsis and revealed chromosome pulverization hotspot regions. The present study further determined 199 genomic locations that were significantly enriched for breakpoints, which indicated TNBC?specific genomic instability regions. Unsupervised hierarchical clustering of tumors resulted in three main subgroups that exhibited distinct CNA profiles, which may reveal the heterogeneity of molecular mechanisms in TNBC subgroups. These results will extend the molecular understanding of TNBC and will facilitate the discovery of therapeutic and diagnostic target candidates.

SUBMITTER: Li Z

PROVIDER: S-EPMC6959384 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Comprehensive identification and characterization of somatic copy number alterations in triple‑negative breast cancer.

Li Zaibing Z Zhang Xiao X Hou Chenxin C Zhou Yuqing Y Chen Junli J Cai Haoyang H Ye Yifeng Y Liu Jinping J Huang Ning N

International journal of oncology 20191223 2

Triple‑negative breast cancer (TNBC) accounts for ~15% of all breast cancer diagnoses each year. Patients with TNBC tend to have a higher risk for early relapse and a worse prognosis. TNBC is characterized by extensive somatic copy number alterations (CNAs). However, the DNA CNA profile of TNBC remains to be extensively investigated. The present study assessed the genomic profile of CNAs in 201 TNBC samples, aiming to identify recurrent CNAs that may drive the pathogenesis of TNBC. In total, 123 ...[more]

PMID: 31894314

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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:INTRODUCTION: Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance. METHODS: High-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data. RESULTS: A core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy number events, irrespective of subtype. Finally, SNP data from individual tumors indicated that genomic amplification in general appears as monoallelic, that is, it preferentially targets one parental chromosome in HER2-amplified tumors. CONCLUSIONS: We have delineated the genomic landscape of CNAs, amplifications, LOH, and CNN-AI in HER2-amplified breast cancer, but also demonstrated a strong association between different types of genomic aberrations and tumor aneuploidy irrespective of molecular subtype.

Dataset Information

Comprehensive identification and characterization of somatic copy number alterations in triple?negative breast cancer.

Publications

Comprehensive identification and characterization of somatic copy number alterations in triple‑negative breast cancer.

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