Dataset Information

Personalized analysis of breast cancer using sample-specific networks.

ABSTRACT: Breast cancer is a disease with high heterogeneity. Cancer is not usually caused by a single gene, but by multiple genes and their interactions with others and surroundings. Estimating breast cancer-specific gene-gene interaction networks is critical to elucidate the mechanisms of breast cancer from a biological network perspective. In this study, sample-specific gene-gene interaction networks of breast cancer samples were established by using a sample-specific network analysis method based on gene expression profiles. Then, gene-gene interaction networks and pathways related to breast cancer and its subtypes and stages were further identified. The similarity and difference among these subtype-related (and stage-related) networks and pathways were studied, which showed highly specific for subtype Basal-like and Stages IV and V. Finally, gene pairwise interactions associated with breast cancer prognosis were identified by a Cox proportional hazards regression model, and a risk prediction model based on the gene pairs was established, which also performed very well on an independent validation data set. This work will help us to better understand the mechanism underlying the occurrence of breast cancer from the sample-specific network perspective.

SUBMITTER: Zhu K

PROVIDER: S-EPMC7233277 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Personalized analysis of breast cancer using sample-specific networks.

Zhu Ke K Pian Cong C Xiang Qiong Q Liu Xin X Chen Yuanyuan Y

PeerJ 20200515

Breast cancer is a disease with high heterogeneity. Cancer is not usually caused by a single gene, but by multiple genes and their interactions with others and surroundings. Estimating breast cancer-specific gene-gene interaction networks is critical to elucidate the mechanisms of breast cancer from a biological network perspective. In this study, sample-specific gene-gene interaction networks of breast cancer samples were established by using a sample-specific network analysis method based on g ...[more]

PMID: 32461838

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Project description:BackgroundHistologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues.MethodsWe present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup.ResultsWe applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set.ConclusionsWe present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at http://csbi.ltdk.helsinki.fi/pub/czliu/DERA/.

Project description:MotivationProtein phosphorylation is a ubiquitous mechanism of post-translational modification that plays a central role in cellular signaling. Phosphorylation is particularly important in the context of cancer, as downregulation of tumor suppressors and upregulation of oncogenes by the dysregulation of associated kinase and phosphatase networks are shown to have key roles in tumor growth and progression. Despite recent advances that enable large-scale monitoring of protein phosphorylation, these data are not fully incorporated into such computational tasks as phenotyping and subtyping of cancers.ResultsWe develop a network-based algorithm, CoPPNet, to enable unsupervised subtyping of cancers using phosphorylation data. For this purpose, we integrate prior knowledge on evolutionary, structural and functional association of phosphosites, kinase-substrate associations and protein-protein interactions with the correlation of phosphorylation of phosphosites across different tumor samples (a.k.a co-phosphorylation) to construct a context-specific-weighted network of phosphosites. We then mine these networks to identify subnetworks with correlated phosphorylation patterns. We apply the proposed framework to two mass-spectrometry-based phosphorylation datasets for breast cancer (BC), and observe that (i) the phosphorylation pattern of the identified subnetworks are highly correlated with clinically identified subtypes, and (ii) the identified subnetworks are highly reproducible across datasets that are derived from different studies. Our results show that integration of quantitative phosphorylation data with network frameworks can provide mechanistic insights into the differences between the signaling mechanisms that drive BC subtypes. Furthermore, the reproducibility of the identified subnetworks suggests that phosphorylation can provide robust classification of disease response and markers.Availability and implementationCoPPNet is available at http://compbio.case.edu/coppnet/.Supplementary informationSupplementary data are available at Bioinformatics online.

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Personalized analysis of breast cancer using sample-specific networks.

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Personalized analysis of breast cancer using sample-specific networks.

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