DETECTION AND CLASSIFICATION OF HUMAN PAPILLOMAVIRUS ASSOCIATED CANCERS
Systems and methods described herein include detecting a presence or absence of HPV in a biological sample having cell-free nucleic acids from a subject and potentially cell-free nucleic acids from an HPV strain. Based on a detection of HPV viral nucleic acids in the biological sample, an HPV-based multiclass classifier that predicts a score for each HPV-associated cancer type is applied. The HPV-based multiclass classifier is trained on a training set of HPV-positive cancer samples. An HPV-associated cancer associated with the biological sample is determined based on the scores predicted by the HPV multiclass classifier.
1 - 11 . (canceled)
12 . A method of screening for presence of an HPV-associated cancer in a subject, comprising:
detecting a presence or absence of HPV in a biological sample comprising cell-free nucleic acids from the subject and potentially cell-free nucleic acids from at least one HPV strain in a set of HPV strains;
based on a detection of HPV viral nucleic acids in the biological sample, applying an HPV-based multiclass classifier that predicts a score for each of a plurality of HPV-associated cancer types, wherein the HPV-based multiclass classifier is trained on a training set comprising HPV-positive cancer samples; and
determining, based on the scores predicted by the HPV multiclass classifier, an HPV-associated cancer associated with the biological sample.
13 . The method according to claim 12 , wherein detecting the presence or absence of HPV viral nucleic acids in the biological sample comprises:
determining an amount of HPV fragments in the biological sample that are derived from the potentially cell-free nucleic acid from the at least one HPV strain in the set of HPV strains;
comparing the amount of HPV fragments to a cutoff; and
detecting HPV presence in the biological sample when the amount exceeds the cutoff.
14 . The method according to claim 12 , wherein determining the amount of HPV fragments comprises:
sequencing the cell-free nucleic acids and potentially cell-free nucleic acids from one or more HPV strains to obtain a plurality of sequence reads; and
determining the amount of HPV fragments based on a total count of the plurality of sequence reads that map to one or more HPV reference genomes corresponding to the one or more HPV strains.
15 . The method according to claim 14 , wherein the sequencing is performed by whole genome sequencing, targeted sequencing, or whole genome bisulfite sequencing.
16 . The method according to claim 13 , wherein the cutoff is a count of at least 6 unique HPV fragments, each unique HPV fragment mapping to an HPV reference genome corresponding to at least one HPV strain in the set of HPV strains.
17 . The method according to claim 12 , wherein the set of HPV strains comprises at least one of HPV 16 or HPV 18.
18 . The method according to claim 12 , wherein the set of HPV strains includes one or more of HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.
19 . The method according to claim 12 , wherein the HPV-based multiclass classifier predicts the scores based on features derived from sequencing the potentially cell-free nucleic acids from the at least one HPV strain in a set of HPV strains in the biological sample, wherein the features comprise one or more of methylation-derived features, a total count of HPV fragments, and a binarized count of HPV fragments.
20 . The method according to claim 19 , wherein the methylation-derived features comprise features that discriminate pairwise comparisons among HPV-associated cancer types and other cancer types, wherein the other cancer types comprise lung cancers.
21 . The method according to claim 19 , wherein the sequencing is performed by whole genome sequencing, targeted sequencing, or whole genome bisulfite sequencing.
22 . The method according to claim 19 , wherein the sequencing is performed by targeted sequencing with a hybridization capture panel containing probes targeting HPV reference genomes corresponding to the set of HPV strains.
23 . The method according to claim 22 , wherein the probes tile the targeted HPV reference genomes.
24 . The method according to claim 12 , wherein the plurality of HPV-associated cancer types comprise cervical, anogenital, and head and neck cancers.
25 . The method according to claim 12 , wherein the HPV-based multiclass classifier comprises a multinomial logistic regression classifier.
26 . The method according to claim 12 , wherein training of the HPV-based multiclass classifier is restricted to the HPV-positive cancer samples, wherein the HPV-positive cancer samples comprise at least one of cervical, anorectal, and head and neck cancers.
27 . The method according to claim 12 , comprising:
based on a detection of HPV absence from the biological sample:
forgoing applying the HPV-based multiclass classifier; or
determining an absence of HPV-associated cancer from the biological sample.
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48 . A non-transitory computer readable storage medium storing instructions that, when executed by a hardware processor, cause the hardware processor to perform steps comprising:
detecting a presence or absence of HPV in a biological sample comprising cell-free nucleic acids from the subject and potentially cell-free nucleic acids from at least one HPV strain in a set of HPV strains;
based on a detection of HPV viral nucleic acids in the biological sample, applying an HPV-based multiclass classifier that predicts a score for each of a plurality of HPV-associated cancer types, wherein the HPV-based multiclass classifier is trained on a training set comprising HPV-positive cancer samples; and
determining, based on the scores predicted by the HPV multiclass classifier, an HPV-associated cancer associated with the biological sample.
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56 . A system for screening for presence of an HPV-associated cancer in a subject, the system comprising a hardware processor and a non-transitory computer-readable storage medium storing instructions that, when executed by the hardware processor, cause the hardware processor to perform steps comprising:
detecting a presence or absence of HPV in a biological sample comprising cell-free nucleic acids from the subject and potentially cell-free nucleic acids from at least one HPV strain in a set of HPV strains;
based on a detection of HPV viral nucleic acids in the biological sample, applying an HPV-based multiclass classifier that predicts a score for each of a plurality of HPV-associated cancer types, wherein the HPV-based multiclass classifier is trained on a training set comprising HPV-positive cancer samples; and
determining, based on the scores predicted by the HPV multiclass classifier, an HPV-associated cancer associated with the biological sample.
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