Detecting cancer, cancer tissue of origin, and/or a cancer cell type

A method of detecting cells of a cancer type in a subject, the method comprising,

• a) capturing cell-free DNA (cfDNA) fragments from the subject or amplification products thereof with a composition comprising a plurality of different bait oligonucleotides, wherein:
• (i) each bait oligonucleotide in the plurality of different bait oligonucleotides is at least 45 nucleotides in length;
• (ii) the plurality of different bait oligonucleotides collectively hybridize to at least 200 target genomic regions;
• (iii) the at least 200 target genomic regions are differentially methylated in at least one cancer type relative to a different cancer type or relative to non-cancer;
• (iv) the at least 200 target genomic regions comprise, for at least 80% of all possible pairs of cancer types selected from a set comprising at least 10 cancer types, at least one target genomic region that is differentially methylated between the pair of cancer types;
• and
• (v) the capturing comprises separating bait-bound DNA from unbound DNA;
• b) sequencing the captured cfDNA fragments or amplification products thereof to produce sequencing reads, and
• c) detecting the cells of the cancer type with a trained classifier, wherein:
• (i) the trained classifier detects a number of sequencing reads above a threshold for a plurality of the at least 200 target genomic regions that are identified as hypermethylated or hypomethylated in the cfDNA fragments;
• (ii) the likelihood of a false-positive determination of cancer is less than 1%, and
• (iii) the likelihood of an accurate assignment of a cancer type is at least 75%.

A method of detecting cells of a cancer type in a subject, the method comprising:

• a) processing cell-free DNA (cfDNA) from a biological sample with a deaminating agent to generate a cfDNA sample comprising deaminated nucleotides;
• b) enriching the cfDNA sample or amplification products thereof for informative cell-free DNA molecules, wherein:
• (i) the enriching comprises contacting the cfDNA sample or amplification products thereof with a plurality of different bait oligonucleotides;
• (ii) each bait oligonucleotide in the plurality of different bait oligonucleotides is at least 45 nucleotides in length;
• and
• (iii) the plurality of different bait oligonucleotides collectively hybridize to at least 100 target genomic regions selected from an one of Lists 1-16, or complements thereof;
• c) sequencing the enriched cfDNA molecules to produce a set of sequencing reads;
• and
• d) detecting sequencing reads for cfDNA molecules from the cells of the cancer type, thereby detecting the cancer cells.