A map of human cancer signaling

Abstract

We conducted a comprehensive analysis of a manually curated human signaling network containing 1634 nodes and 5089 signaling regulatory relations by integrating cancer-associated genetically and epigenetically altered genes. We find that cancer mutated genes are enriched in positive signaling regulatory loops, whereas the cancer-associated methylated genes are enriched in negative signaling regulatory loops. We further characterized an overall picture of the cancersignaling architectural and functional organization. From the network, we extracted an oncogenesignaling map, which contains 326 nodes, 892 links and the interconnections of mutated and methylated genes. The map can be decomposed into 12 topological regions or oncogene-signaling blocks, including a few 'oncogene-signaling-dependent blocks' in which frequently used oncogenesignaling events are enriched. One such block, in which the genes are highly mutated and methylated, appears in most tumors and thus plays a central role in cancer signaling. Functional collaborations between two oncogene-signaling-dependent blocks occur in most tumors, although breast and lung tumors exhibit more complex collaborative patterns between multiple blocks than other cancer types. Benchmarking two data sets derived from systematic screening of mutations in tumors further reinforced our findings that, although the mutations are tremendously diverse and complex at the gene level, clear patterns of oncogene-signaling collaborations emerge recurrently at the network level. Finally, the mutated genes in the network could be used to discover novel cancerassociated genes and biomarkers.

Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer

“…Recently, Cui et al (50) constructed a cancer signaling map. Interestingly, several of the genes we have validated were mapped near a Ras subnetwork and were directly or indirectly related to p38 kinase, a protein described previously to be involved in oxaliplatin-related apoptotic mechanisms (9).…”

“…21. The data reported in Table 1 represent the oxaliplatin IC 50 mean F SD of a minimum of three independent experiments with 8 wells at each drug concentration tested.…”

“…The isolation of HTOXAR3, LoVOXAR3, DLDOXAR3, and LSOXAR3 was started with an initial continuous exposure of their sensitive colorectal cancer parental cells HT29, LoVo, DLD1, and LS513 to their respective oxaliplatin IC 50 as described previously in ref. 18.…”

Predicting potential cancer genes by integrating network properties, sequence features and functional annotations

“…The selected interactions were all obtained experimentally and interactions based only on prediction results were excluded. This interaction dataset was integrated with a previous reported human signaling network that contained 1643 nodes and 5089 signaling regulatory relations [15]. The total number of PPIs and number of unique proteins in the final dataset was 47757 and 10016, respectively.…”

Parallel Real-Time PCR on a Chip for Genetic Tug-of-War (gTOW) Method

“…Knowledge obtained from the gTOW method is important for understanding of biology at the system level. [12][13][14] The gTOW method analysis is useful exploring the foundation of biological systems such as biological robustness.…”