Identification of sample-specific regulations using integrative network level analysis.
BACKGROUND
Histologically 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.


METHODS
We 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.


RESULTS
We 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.


CONCLUSIONS
We 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/.
Research Programs Unit, Genome-Scale Biology Research Program and Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, Helsinki, FI-00014, Finland. Chengyu.Liu@helsinki.fi.
Chengyu
C
Liu
Research Programs Unit, Genome-Scale Biology Research Program and Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, Helsinki, FI-00014, Finland. Riku.Louhimo@helsinki.fi.
Riku
R
Louhimo
Research Programs Unit, Genome-Scale Biology Research Program and Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, Helsinki, FI-00014, Finland. marko@significo.fi.
Marko
M
Laakso
Research Programs Unit, Genome-Scale Biology Research Program and Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, Helsinki, FI-00014, Finland. Rainer.Lehtonen@helsinki.fi.
Rainer
R
Lehtonen
Research Programs Unit, Genome-Scale Biology Research Program and Institute of Biomedicine, University of Helsinki, Haartmaninkatu 8, Helsinki, FI-00014, Finland. Sampsa.Hautaniemi@helsinki.fi.
Sampsa
S
Hautaniemi
D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D057089:Pathology, Molecular; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology