Methods for early detection of cancer

A method for detecting residual cancer after surgery by interrogating methylation status and genetic variants in cell-free deoxyribonucleic acid (cfDNA) molecules of a sample from a subject, the method comprising:

• (a) enriching the cfDNA molecules or amplicons thereof using oligonucleotide sequence capture probes for a plurality of genes or genomic regions, wherein the plurality of genes or genomic regions:
• (i) comprise CpG islands which are differentially methylated regions, and
• (ii) are known to be associated with one or more cancers;
• (b) sequencing a plurality of enriched cfDNA molecules or enriched amplicons thereof to generate sequencing data;
• and
• (c) determining methylation profiles of the cfDNA molecules from the sequencing data and further detecting a presence or absence of one or more genetic variants in cfDNA molecules in the sample to detect the presence or absence of residual disease in the subject.