Pan-cancer comparative and integrative analyses of driver alterations using Japanese and international genomic databases.

Using 48,627 samples from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), we present a pan-cancer landscape of driver alterations and their clinical actionability in Japanese patients. Comparison with Whites in Genomics Evidence Neoplasia Information Exchange (GENIE) demonstrates high TP53 mutation frequencies in Asians across multiple cancer types. Integration of C-CAT, GENIE, and The Cancer Genome Atlas data reveals many co-occurring and mutually exclusive relationships between driver mutations. At pathway level, mutations in epigenetic regulators frequently co-occur with PI3K pathway molecules. Furthermore, we found significant co-occurring mutations within the epigenetic pathway. Accumulation of mutations in epigenetic regulators causes increased proliferation-related transcriptomic signatures. Loss-of-function of many epigenetic drivers inhibits cell proliferation in their wild-type cell lines, but this effect is attenuated in those harboring mutations of not only the same but also different epigenetic drivers. Our analyses dissect various genetic properties and provide valuable resources for precision medicine in cancer.