Modeling the cancer transcriptome.
Recent initiatives such as The Cancer Genome Atlas have mapped the genome-wide effect of individual genes on tumor growth. By unraveling genomic alterations in tumors, molecular subtypes of cancers have been identified, which is improving patient diagnostics and treatment.
Uhlen et al. developed a computer-based modeling approach to examine different cancer types in nearly 8000 patients. They provide an open-access resource for exploring how the expression of specific genes influences patient survival in 17 different types of cancer.
More than 900,000 patient survival profiles are available, including for tumors of colon, prostate, lung, and breast origin. This interactive data set can also be used to generate personalized patient models to predict how metabolic changes can influence tumor growth.
Cancer is a leading cause of death worldwide, and there is great need to define the molecular mechanisms driving the development and progression of individual tumors. The Hallmarks of Cancer has provided a framework for a deeper molecular understanding of cancer, and the focus so far has been on the genetic alterations in individual cancers, including genome rearrangements, gene amplifications, and specific cancer-driving mutations. Using systems-level approaches, it is now also possible to define downstream effects of individual genetic alterations in a genome-wide manner.
In our study, we used a systems-level approach to analyze the transcriptome of 17 major cancer types with respect to clinical outcome, based on a genome-wide transcriptomics analysis of ~8000 individual patients with clinical metadata. The study was made possible through the availability of large open-access knowledge-based efforts such as the Cancer Genome Atlas and the Human Protein Atlas. Here, we used the data to perform a systems-level analysis of 17 major human cancer types, describing both interindividual and intertumor variation patterns.
The analysis identified candidate prognostic genes associated with clinical outcome for each tumor type; the results show that a large fraction of cancer protein-coding genes are differentially expressed and, in many cases, have an impact on overall patient survival. Systems biology analyses revealed that gene expression of individual tumors within a particular cancer varied considerably and could exceed the variation observed between distinct cancer types. No general prognostic gene necessary for clinical outcome was applicable to all cancers. Shorter patient survival was generally associated with up-regulation of genes involved in mitosis and cell growth and down-regulation of genes involved in cellular differentiation. The data allowed us to generate personalized genome-scale metabolic models for cancer patients to identify key genes involved in tumor growth. In addition, we explored tissue-specific genes associated with the dedifferentiation of tumor cells and the role of specific cancer testis antigens on a genome-wide scale. For lung and colorectal cancer, a selection of prognostic genes identified by the systems biology effort were analyzed in independent, prospective cancer cohorts using immunohistochemistry to validate the gene expression patterns at the protein level.
A Human Pathology Atlas has been created as part of the Human Protein Atlas program to explore the prognostic role of each protein-coding gene in 17 different cancers. Our atlas uses transcriptomics and antibody-based profiling to provide a standalone resource for cancer precision medicine. The results demonstrate the power of large systems biology efforts that make use of publicly available resources. Using genome-scale metabolic models, cancer patients are shown to have widespread metabolic heterogeneity, highlighting the need for precise and personalized medicine for cancer treatment. With more than 900,000 Kaplan-Meier plots, this resource allows exploration of the specific genes influencing clinical outcome for major cancers, paving the way for further in-depth studies incorporating systems-level analyses of cancer. All data presented are available in an interactive open-access database (www.proteinatlas.org/pathology) to allow for genome-wide exploration of the impact of individual proteins on clinical outcome in major human cancers.