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US 2021/0262016 A1Published application
Methods and systems for somatic mutations and uses thereof
AssigneeMyriad Genetics, Inc.
InventorsAndrey ZHARKIKH, Kirsten TIMMS, Michael PERRY, Alexander GUTIN
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Abstract
This invention provides methods and compositions for detecting somatic mutations in cancer cells. The methods can be used for measuring tumor mutation burden. Provided are methods for identifying and treating subjects who benefit from treatment with anticancer agents such as immune checkpoint inhibitors, methods for treating cancer in a subject, and methods for monitoring and prognosing a subject having cancer.
Claims58
A method for detecting a somatic variant, comprising:
- (a) sequencing cells of a sample;
- (b) identifying a set of heterozygous SNP positions, wherein each SNP has alleles B and A;
- (c) detecting two germline allele parings for a SNP position and a variant in a position near the SNP position, wherein the two germline allele parings are (i) allele B and a first variant allele, and (ii) allele A and a second variant allele which may the same or different than the first variant allele;
- and
- (d) detecting a third allele pairing which is (iii) allele B and a third variant allele that is different from the first variant allele.
2 more elements
A method for detecting a somatic variant, comprising:
- (a) sequencing cells of a tumor sample;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- and
- (e) calculating a somatic mutation significance score (S) for the third element.
3 more elements
A method for identifying a subject having cancer who benefits from a treatment, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) identifying a set of heterozygous SNP positions, wherein each SNP has alleles B and A;
- (c) detecting two germline allele parings for a SNP position and a variant in a position near the SNP position, wherein the two germline allele parings are (i) allele B and a first variant allele, and (ii) allele A and a second variant allele which may the same or different than the first variant allele;
- and
- (d) detecting a third allele pairing which is (iii) allele B and a third variant allele that is different from the first variant allele, wherein the third allele pairing arises from a somatic variant;
- (f) calculating a value for a tumor mutation burden from the somatic variants detected from the allele pairings;
- and
- (g) identifying the subject having cancer who benefits from a treatment who has the tumor mutation burden greater than a reference level.
5 more elements
A method for identifying a subject having cancer who benefits from a treatment, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- and
- (f) identifying the subject having cancer who benefits from a treatment who has the tumor mutation burden greater than a reference level of somatic mutation.
7 more elements
A method for treating cancer in a subject in need thereof, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) identifying a set of heterozygous SNP positions, wherein each SNP has alleles B and A;
- (c) detecting two germline allele parings for a SNP position and a variant in a position near the SNP position, wherein the two germline allele parings are (i) allele B and a first variant allele, and (ii) allele A and a second variant allele which may the same or different than the first variant allele;
- and
- (d) detecting a third allele pairing which is (iii) allele B and a third variant allele that is different from the first variant allele, wherein the third allele pairing arises from a somatic variant;
- (e) calculating a value for a tumor mutation burden from the somatic variants detected;
- (f) identifying the subject having cancer who benefits from a treatment who has the tumor mutation burden greater than a reference level;
- and
- (g) administering a treatment for cancer.
6 more elements
A method for treating cancer in a subject in need thereof, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- (f) identifying the subject having cancer who will benefit from a treatment who has the tumor mutation burden greater than a reference level of somatic mutation;
- and
- (g) administering a treatment for cancer.
8 more elements
A method for treating cancer in a subject in need thereof, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- (f) identifying a subject having cancer who will benefit from a treatment who has the tumor mutation burden greater than a reference level of somatic mutation;
- (g) monitoring the subject for the signs and symptoms of cancer for a period of time;
- and
- (h) administering a treatment for cancer.
9 more elements
A method for monitoring a response of a subject having cancer to a treatment, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) identifying a set of heterozygous SNP positions, wherein each SNP has alleles B and A;
- (c) detecting two germline allele parings for a SNP position and a variant in a position near the SNP position, wherein the two germline allele parings are (i) allele B and a first variant allele, and (ii) allele A and a second variant allele which may the same or different than the first variant allele;
- and
- (d) detecting a third allele pairing which is (iii) allele B and a third variant allele that is different from the first variant allele, wherein the third allele pairing arises from a somatic variant;
- (e) calculating a value for a tumor mutation burden from the somatic variants detected.
3 more elements
A method for monitoring a response of a subject having cancer to a treatment, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions.
5 more elements
A method for prognosing a subject having cancer, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) identifying a set of heterozygous SNP positions, wherein each SNP has alleles B and A;
- (c) detecting two germline allele parings for a SNP position and a variant in a position near the SNP position, wherein the two germline allele parings are (i) allele B and a first variant allele, and (ii) allele A and a second variant allele which may the same or different than the first variant allele;
- and
- (d) detecting a third allele pairing which is (iii) allele B and a third variant allele that is different from the first variant allele, wherein the third allele pairing arises from a somatic variant;
- (e) calculating a value for a tumor mutation burden from the somatic variants detected;
- and
- (f) prognosing the subject as having a poor prognosis who has the tumor mutation burden greater than a TMB reference level.
5 more elements
A method for prognosing a subject having cancer, the method comprising:
- (a) sequencing cells of a tumor sample from the subject;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- (f) prognosing the subject as having a poor prognosis who has the tumor mutation burden greater than a TMB reference level;
- and
- (g) administering a treatment for cancer.
8 more elements
A kit for identifying a subject having cancer who benefits from a treatment, the kit comprising:
- (a) reagents for obtaining sequence reads from a sample from the subject, wherein the sequence reads can be used to obtain a value for a tumor mutation burden of the sample;
- and
- (b) instructions for using the reagents for obtaining the sequence reads and the value for a tumor mutation burden for identifying the subject.
A system for detecting a somatic variant, comprising:
- means for receiving, enriching and amplifying a nucleic acid from a sample, wherein the sample contains cancer cells and non-cancer cells;
- means for synthesizing a library from the nucleic acid;
- means for contacting the library with a sequencing chip;
- means for detecting a sequence in the library and transferring sequence data to a processor;
- one or more processors for carrying out the steps:
- (a) providing a sample which contains cancer cells and non-cancer cells;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- and
- a display for displaying, charting and reporting sequence information.
12 more elements
A non-transitory machine-readable storage medium having stored therein instructions for execution by a processor which cause the processor to perform the steps of a method for detecting a somatic variant, the method comprising:
- (a) providing a sample which contains cancer cells and non-cancer cells;
- (b) obtaining sequence reads from the sample using a massively parallel nucleic acid sequencing process, wherein the sequence reads have a read length;
- (c) mapping the sequence reads to a reference genome;
- (d) assembling a somatic variant count matrix of sequence reads that are mapped to a heterozygous-SNP position of the reference genome, wherein the count matrix has first and second elements which count allele pairings of SNP alleles B and A, respectively, to a variant allele, and wherein the count matrix has a third element which counts read sequences from SNP allele B paired to a different variant allele than in the first element;
- (e) calculating a value for a tumor mutation burden of the sample by the steps:
- (i) calculating a somatic mutation significance score (S) for the third element for each somatic variant;
- and
- (ii) calculating the value for the tumor mutation burden from the number of somatic variants having a somatic mutation significance score above a threshold, normalized by the total number of positions in the heterozygous-SNP regions;
- and
- (f) displaying, charting and reporting sequence information from the sample.
7 more elements
Dependencies are inferred from the claim text.