Translating clinical gene sequencing into a foundational representation of tumor subtype

Abstract While gene sequencing is routine in cancer care, translating sequences into treatment decisions remains a challenge. Here we introduce MutationProjector, an AI foundation model that transforms tumor mutation profiles into a compact representation of cancer subtype, with broad implications for diagnosis and therapy. MutationProjector is pre-trained by integrating genomic alterations from >30,000 tumors with extensive molecular knowledge, yielding a model that accurately reconstructs held-out genetic profiles (demonstrating strong generalization) and determines subtype representations from altered molecular pathways (enabling model interpretability). We evaluate MutationProjector in independent tasks related to prediction of immunotherapy response, prediction of chemotherapy response, and classification of metastasis, recording leading performance in all areas. Each task identifies key biomarkers of interest, including KMT2A and KRAS-STK11 alterations which govern immunotherapy response. Competing Interest Statement T.I. is a co-founder, member of the advisory board, and has an equity interest in Data4Cure and Serinus Biosciences. T.I. is also a consultant for and has an equity interest in Ideaya Biosciences and Eikon Therapeutics. The terms of these arrangements have been reviewed and approved by the University of California San Diego in accordance with its conflict-of-interest policies. J.M. and C.A. are employees at Lunit. C.O. holds a leadership role and is a stockholder at Lunit.