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

A method for detecting cells of a hematological disorder (HD) in a subject, the method comprising

• a) capturing cell-free DNA (cfDNA) fragments from the test-subject or amplification products thereof with a bait oligonucleotide composition, wherein:
• i) the bait oligonucleotide composition comprises a plurality of different bait oligonucleotides that collectively hybridize to at least 100 target genomic regions;
• ii) each bait oligonucleotide of the plurality of different bait oligonucleotides is at least 45 nucleotides in length;
• iii) the at least 100 target genomic regions are differentially methylated in at least one HD relative to a different HD or relative to a non-HD cancer;
• iv) the at least one HD and the different HD are selected from leukemia, lymphoid neoplasm, multiple myeloma, and myeloid neoplasm;
• and
• v) 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) applying-detecting cells of the first HD with a trained classifier, wherein the trained classifier detects a number of sequencing reads above a threshold for a plurality of the at least 100 target genomic regions that are identified as hypermethylated or hypomethylated in the ctDNA fragments.

A hematological disorder (HD) assay panel, comprising:

• at least 500 pairs of probes, wherein each pair of the at least 500 pairs comprise two probes configured to overlap each other by an overlapping sequence,
• wherein the overlapping sequence comprises a sequence of at least 30-nucleotides,
• wherein the at least 30-nucleotide sequence is configured to hybridize to a converted cfDNA molecule corresponding to, or derived from one or more of genomic regions,
• wherein each of the genomic regions comprises at least five methylation sites, and
• wherein the at least five methylation sites have an abnormal methylation pattern in HD samples.