Liquid biopsy informed precision oncology is the cornerstone for increasing the survival chances of cancer patients and improving their quality of life. Unfortunately, tools for ultra-sensitive (“DEEP”) and affordable detection of somatic mutations with short turnaround times in the patients' blood plasma are largely lacking. In the proposed project, a complementary consortium of experts will develop and validate an innovative  ‘universal’ digital PCR (“DIG”) mutation quantification technology. This technology will then form the basis for further developments for higher-order multiplexing, adjacent hotspot mutations, and application on circulating DNA from liquid biopsies. To analyze the higher-order multiplexing digital PCR data, a novel powerful algorithm and software will be developed and tested on experimental data from various digital PCR platforms. Finally, a prospectively collected clinical sample cohort along with treatment response information will be used to demonstrate clinical validity of the novel precision oncology tool of longitudinal monitoring of private somatic mutations in cancer patients’ blood plasma. As proof-of-principle, DIG-DEEP will focus on pancreatic cancer and pediatric cancer.