A foundation model of cancer genotype enables precise predictions of therapeutic response

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Abstract
While genetic sequencing is routine in cancer care, translating a tumor’s complex mutation profile into actionable treatment decisions remains a central challenge. MutationProjector is pre-trained from a large corpus of genomic alterations across 30,000+ tumors, integrated with extensive molecular knowledge. The resulting projection reveals a tumor’s altered molecular pathways, facilitating model interpretation, and it accurately reconstructs held-out mutations, demonstrating model generalization. When applied to predict immunotherapy or chemotherapy resistance across multiple cancer types and cohorts, MutationProjector achieves or exceeds state-of-the-art performance in all contexts. It identifies unexpected biomarkers, including KMT2D mutation in immunotherapy sensitivity and joint alteration of SMARCA4 and STK11 in immunotherapy resistance. These results establish a unifying framework for connecting tumor genotypes to biological mechanisms and therapeutic outcomes.
Funding Information
  • Advanced Research Projects Agency for Health (OT 140D042590013)
  • National Institutes of Health (T32CA121938)
  • National Institutes of Health (U54CA274502)
  • National Institutes of Health (R01ES014811)

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