SUITOR: selecting the number of mutational signatures through cross-validation

Abstract For de novo mutational signature analysis, the critical first step is to decide how many signatures should be expected in a cancer genomics study. An incorrect number could mislead downstream analyses. Here we present SUITOR (selecting the number of mutational signatures through cross-validation), an unsupervised cross-validation method that requires little assumptions and no numerical approximations to select the optimal number of signatures without overfitting the data. In vitro studies and in silico simulations demonstrated that SUITOR can correctly identify signatures, some of which were missed by other widely used methods. Applied to 1,536 whole-genome sequenced tumors across eight cancer types, SUITOR selected signatures with the smallest prediction errors and almost all signatures of breast cancer selected by SUITOR were validated in an independent study. SUITOR is a powerful tool to select the optimal number of mutational signatures, facilitating downstream analyses with etiological or therapeutic importance.