The implementation of cancer precision medicine requires biomarkers or signatures for predicting prognosis and therapeutic benefits.Most of current efforts in this field are paying much more attention to predictive accuracy than to molecular mechanistic interpretability.Mechanism-driven strategy has recently emerged,aiming to build signatures with both predictive power and explanatory power.Driven by this strategy,we developed a robust gene dysregulation analysis framework with machine learning algorithms,which is capable of exploring gene dysregulations underlying carcinogenesis from high-dimensional data with cooperativity and synergy between regulators and several other transcriptional regulation rules taken into consideration.We then applied the framework to a colorectal cancer (CRC) cohort from The Cancer Genome Atlas.The identified CRC-related dysregulations significantly covered known carcinogenic processes and exhibited good prognostic effect.By choosing dysregulations with greedy strategy,we built a four-dysregulation (4-DysReg) signature,which has the capability of predicting prognosis and adjuvant chemotherapy benefit.4-DysReg has the potential to explain carcinogenesis in terms of dysfunctional transcriptional regulation.These results demonstrate that our gene dysregulation analysis framework could be used to develop predictive signature with mechanistic interpretability for cancer precision medicine,and furthermore,elucidate the mechanisms of carcinogenesis.