Abstract: Aspects of the invention include methods and systems for identifying somatic mutational signatures for detecting, diagnosing, monitoring and/or classifying cancer in a patient known to have, or suspected of having cancer. In various embodiments, the methods of the invention use a non-negative matrix factorization (NMF) approach to construct a signature matrix that can be used to identify latent signatures in a patient sample for detection and classification of cancer. In some embodiments, the methods of the invention may use principal components analysis (PCA) or vector quantization (VQ) approaches to construct a signature matrix.