Abstract
Gaining insight into the mechanisms of signal transduction networks (STNs) by using critical features from patient-specific mathematical models can improve patient stratification and help to identify potential drug targets. To achieve this, these models should focus on the critical STNs for each cancer, include prognostic genes and proteins, and correctly predict patient-specific differences in STN activity. Focussing on colorectal cancer and the WNT STN, we used mechanism-based machine learning models to identify genes and proteins with significant associations to event-free patient survival and predictive power for explaining patient-specific differences of STN activity. First, we identified the WNT pathway as the most significant pathway associated with event-free survival. Second, we built linear-regression models that incorporated both genes and proteins from established mechanistic models in the literature and novel genes with significant associations to event-free patient survival. Data from The Cancer Genome Atlas and Clinical Proteomic Tumour Analysis Consortium were used, and patient-specific STN activity scores were computed using PROGENy. Three linear regression models were built, based on; (1) the gene-set of a state-of-the-art mechanistic model in the literature, (2) novel genes identified, and (3) novel proteins identified. The novel genes and proteins were genes and proteins of the extant WNT pathway whose expression was significantly associated with event-free survival. The results show that the predictive power of a model that incorporated novel event-free associated genes is better compared to a model focussing on the genes of a current state-of-the-art mechanistic model. Several significant genes that should be integrated into future mechanistic models of the WNT pathway are DVL3, FZD5, RAC1, ROCK2, GSK3B, CTB2, CBT1, and PRKCA. Thus, the study demonstrates that using mechanistic information in combination with machine learning can identify novel features (genes and proteins) that are important for explaining the STN heterogeneity between patients and their association to clinical outcomes.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide [1,2,3]
We developed adjustable linear regression machine learning models of the activation of the canonical WNT signalling pathway and incorporated genes and proteins that were significantly associated with event-free patient survival in CRC
Building upon this work that describes the initial steps of WNT pathway activation, our work builds upon this by identifying new features and regression models that describe the heterogeneity of the WNT pathway activity scores across patients from two CRC cohorts [27]
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide [1,2,3]. From the four global consensus molecular subtypes (CMS) of CRC, CMS1–4, no specific drugs have been identified that target a specific CMS [4]. Biomarkers are foundations of clinical and personalised medicine; despite being vital tools in the area of clinical diagnostics, many are based on single timepoint measurements and lack the dynamic information that is needed to follow diseases and therapy [9]. We hypothesised that by integrating tumour profiling data with dynamic information about signal transduction networks (STNs), mechanism-based machine learning models could aid in the prediction of patient survival and response to therapy, and overall provide insight into the disease and drug-response mechanisms and reveal potential drug targets and novel biomarkers
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