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Published on: June 27, 2020
The functional cancer map: a systems-level synopsis of genetic deregulation in cancer
Markus Krupp1, Thorsten Maass, Jens U Marquardt
1Department of Medicine I, Johannes Gutenberg University, Mainz, Germany. kruppm@uni-mainz.de
Background:
Cancer cells are characterized by massive dysegulation of physiological cell functions with considerable disruption of transcriptional regulation. Genome-wide transcriptome profiling can be utilized for early detection and molecular classification of cancers. Accurate discrimination of functionally different tumor types may help to guide selection of targeted therapy in translational research. Concise grouping of tumor types in cancer maps according to their molecular profile may further be helpful for the development of new therapeutic modalities or open new avenues for already established therapies.
Methods:
Complete available human tumor data of the Stanford Microarray Database was downloaded and filtered for relevance, adequacy and reliability. A total of 649 tumor samples from more than 1400 experiments and 58 different tissues were analyzed. Next, a method to score deregulation of KEGG pathway maps in different tumor entities was established, which was then used to convert hundreds of gene expression profiles into corresponding tumor-specific pathway activity profiles. Based on the latter, we defined a measure for functional similarity between tumor entities, which yielded to phylogeny of tumors.
Results:
We provide a comprehensive, easy-to-interpret functional cancer map that characterizes tumor types with respect to their biological and functional behavior. Consistently, multiple pathways commonly associated with tumor progression were revealed as common features in the majority of the tumors. However, several pathways previously not linked to carcinogenesis were identified in multiple cancers suggesting an essential role of these pathways in cancer biology. Among these pathways were 'ECM-receptor interaction', 'Complement and Coagulation cascades', and 'PPAR signaling pathway'.
Conclusion:
The functional cancer map provides a systematic view on molecular similarities across different cancers by comparing tumors on the level of pathway activity. This work resulted in identification of novel superimposed functional pathways potentially linked to cancer biology. Therefore, our work may serve as a starting point for rationalizing combination of tumor therapeutics as well as for expanding the application of well-established targeted tumor therapies.
Insights
This study created a functional cancer map by analyzing gene expression data from 649 tumor samples. The map reveals new pathways involved in cancer, aiding targeted therapy development.
Area of Science:
- Genomics
- Cancer Biology
- Bioinformatics
Background:
- Cancer exhibits significant dysregulation of cellular functions and transcriptional regulation.
- Genome-wide transcriptome profiling aids in early cancer detection and molecular classification.
- Distinguishing tumor types by molecular profiles can guide targeted therapy selection.
Purpose of the Study:
- To develop a comprehensive functional cancer map based on molecular profiles.
- To identify novel pathways involved in cancer biology.
- To facilitate the rational combination of tumor therapeutics.
Main Methods:
- Downloaded and filtered human tumor data from the Stanford Microarray Database (649 samples, 58 tissues).
- Developed a method to score deregulation of KEGG pathway maps in tumor entities.
- Converted gene expression profiles into tumor-specific pathway activity profiles to determine functional similarity and tumor phylogeny.
Main Results:
- Generated an interpretable functional cancer map characterizing tumor types by biological and functional behavior.
- Identified common pathways associated with tumor progression across most tumors.
- Discovered novel pathways, including 'ECM-receptor interaction', 'Complement and Coagulation cascades', and 'PPAR signaling pathway', implicated in multiple cancers.
Conclusions:
- The functional cancer map offers a systematic view of molecular similarities across cancers via pathway activity comparison.
- Identified novel superimposed functional pathways potentially linked to cancer biology.
- Provides a foundation for rationalizing combination therapies and expanding applications of established targeted therapies.
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