Genomic and clinical landscape of 10,000 Korean pan-cancer patients reveals molecular determinants of prognosis and therapeutic response: K-MASTER program

Precision oncology relies on molecular characterization of the tumors to guide individualized therapy. Although large-scale precision oncology programs have revealed profound insights into the molecular complexity of human cancers, their direct clinical impact remains incompletely defined. Building upon our prior work, we expanded the K-MASTER program, one of the world's largest East Asian pan-cancer cohorts, integrating deep molecular profiling with long-term clinical outcomes. We analyzed 10,000 Korean patients with advanced malignancies, combining molecular aberrations with eight years of survival, treatment modalities, and therapeutic response data. Comparative analyses with the Western cohort, including AACR-GENIE, uncovered ancestry-specific molecular disparities. Furthermore, we developed a unified metric, the Molecular-Prognostic Index (MPI), to systematically quantify and compare the prognostic impact of individual genomic alterations at both pan-cancer and individual tumor levels. Using this framework, we identified key alterations and pathways shaping patient survival and therapeutic sensitivities. Korean cancer patients exhibited distinct molecular features, including frequent CDKN2A loss and mismatch repair deficiency-related mutational signatures. Prognostic modeling revealed that actional alterations curated in OncoKB and APC mutations conferred favorable clinical outcomes, whereas mutations in TP53, CDKN2A, KRAS, and SMARCB1 were significantly associated with poor survival across multiple tumor types. Machine-learning-based analyses further identified DNA damage repair deficiency and chromosomal instability as robust predictors of response to platinum-based chemotherapy and immune checkpoint blockades. Collectively, these results provide unprecedented insights into the complex molecular and clinical landscape of Korean advanced cancers, establish a population-specific framework for precision oncology therapy, and provide mechanistic and prognostic insights essential for global translation of genomic medicine.