This technology includes a panel of 46 genomic loci of DNA methylation (represented by CpG dinucleotides on different chromosomes) with application in blood-based cancer screening. The markers robustly distinguish tumor from normal samples using 8 loci and classify 13 different tumor types. Using 39 loci, inventors were able to discriminate between individual tumor types or peripheral blood. In 4052 tumor samples from 13 tumor types, the true positive rate of classification was 91.4%. The false positive rate was 1.2% from 11 normal tissue types (in 646 samples) and 0% using 2711 normal peripheral blood samples. Furthermore, the 39 loci correctly identify the tumor type with a median rate of > 85%. Computational validation occurred in 8 additional DNA methylation datasets including colon, kidney, lung, liver, pancreas, prostate, and breast.