HiTAIC: hierarchical tumor artificial intelligence classifier traces tissue of origin and tumor type in primary and metastasized tumors using DNA methylation

Human cancers are heterogenous by their cell composition and origination site. Cancer metastasis generates the conundrum of the unknown origin of migrated tumor cells. Tracing tissue of origin and tumor type in primary and metastasized cancer is vital for clinical significance. DNA methylation alterations play a crucial role in carcinogenesis and mark cell fate differentiation, thus can be used to trace tumor tissue of origin. In this study, we employed a novel tumor-type-specific hierarchical model using genome-scale DNA methylation data to develop a multilayer perceptron model, HiTAIC, to trace tissue of origin and tumor type in 27 cancers from 23 tissue sites in data from 7735 tumors with high resolution, accuracy, and specificity. In tracing primary cancer origin, HiTAIC accuracy was 99% in the test set and 93% in the external validation data set. Metastatic cancers were identified with a 96% accuracy in the external data set. HiTAIC is a user-friendly web-based application through https://sites.dartmouth.edu/salaslabhitaic/. In conclusion, we developed HiTAIC, a DNA methylation-based algorithm, to trace tumor tissue of origin in primary and metastasized cancers. The high accuracy and resolution of tumor tracing using HiTAIC holds promise for clinical assistance in identifying cancer of unknown origin.