Abstract: The present disclosure provides methods and systems directed to detection of prostate cancer. A method for processing or analyzing DNA molecules from a biological sample of a subject may comprise processing (a) providing a first set of DNA fragments derived from a first portion of the DNA molecules upon subjecting the first portion to CpG site fragmentation conditions; (b) providing a second set of DNA fragments derived from a second portion of the DNA molecules, the second portion not subjected to fragmentation conditions; (c) for a genomic region, processing the first and the second sets of DNA fragments or derivatives thereof to yield first and second quantitative measures of DNA methylation; and (d) processing the first quantitative measure with the second quantitative measure to yield a third quantitative measure of DNA methylation at the genomic region, thereby generating a methylation profile of the DNA molecules at the genomic region.