Abstract
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/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1265-2) contains supplementary material, which is available to authorized users.
Highlights
Similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data
The breast cancer subtypes have different standard drug treatments based on marker protein expression: human epidermal growth factor receptor 2 (HER2) breast cancers are treated with HER2 inhibitors, such as trastuzumab, whereas luminal breast cancers are treated with adjuvant endocrine therapy, such as aromatase inhibitors
The aims of the ovarian cancer case study were to test robustness of Differentially Expressed Regulation Analysis (DERA) and compare regulations identified in ovarian cancer to triple negative breast cancer (TNBC) as they are recently suggested to share similar molecular characteristics [13]
Summary
Similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. Novel measurement technologies, such as microarrays and deep sequencing, provide quantitative genome-scale data from diseases, such as cancers, in an unprecedented resolution and speed. In cancers, genome-scale studies have revealed large molecular heterogeneity between patients and even different samples from the very same tumor [1]. Protein expression markers have been used many years in clinics, for example in breast cancer, to classify tumors into main subtypes to guide selection of first line drug treatment, genome wide data have significantly facilitated more detailed subtyping and and identification of associated pathways and subsequently novel drug targets. TNBC has contrasting features as there is no beneficial standard therapy for majority of patients, probably reflecting the heterogeneity of this subtype [3]
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