Further refinement of this matrix risk signature to specifically predict which lesions will progress to cancer identified a minimum 6-gene risk signature of RSPO1, CTHRC1, SPP1, MMRN1, COL10A1, and PRG4 as the most significant matrisomal predictors of premalignant progression with a ROC AUC of 0.99 (Additional file 1: Table S3, Fig. S3D). This evidence concerns the gene RSPO1 and cancer.