US 9,792,403 B2Granted

Analysis of genetic variants

AssigneeFoundation Medicine, Inc.

InventorsJames Xin Sun, Roman Yelensky

Life of this patent

Estimating the term…

Abstract

Methods and systems for analyzing genetic variants are disclosed.

Claims22

Dependent claims

A method of characterizing a variant in a tumor sample from a subject as being a somatic or germline event, the method comprising:

a) sequencing each of a plurality of selected subgenomic intervals, each of a plurality of selected germline SNPs, and a variant, wherein the average sequence coverage prior to normalization is at least about 250×;
b) acquiring:
i) a sequence coverage input (SCI), which comprises, for each of the plurality of selected subgenomic intervals, a value for normalized sequence coverage at the selected subgenomic intervals, wherein SCI comprises a comparison of the number of reads for a subgenomic interval with the number of reads for a process-matched control;
ii) an SNP allele frequency input (SAFI), which comprises, for each of the plurality of selected germline SNPs, a value for a minor allele frequency in the tumor sample;
and
iii) for said variant being characterized, a variant allele frequency input (VAFI), which comprises the allele frequency for said variant in the tumor sample;
c) acquiring values, as a function of SCI and SAFI, for:
a genomic segment total copy number (C) for each of a plurality of genomic segments;
a genomic segment minor allele copy number (M) for each of the plurality of genomic segments;
and
sample purity (p),
wherein SCI, SAFI, C, M, and p are related to one another by the following:
r
ij
∼
N
(
log
2
⁢
p
*
C
i
+
(
1
-
p
)
*
2
p
*
(
∑
i
⁢
l
i
⁢
c
i
)
/
∑
i
⁢
l
i
+
(
1
-
p
)
*
2
,
σ
ri
,
and
⁢
⁢
fik
∼
N
⁡
(
p
*
Mi
+
(
1
-
p
)
*
1
p
*
Ci
+
(
1
-
p
)
*
2
,
σ
⁢
⁢
fi
)
,
when SCI and SAFI are notated as rij and fik, respectively;
and
where rij is the log ratio (LR) of subgenomic interval j within a genomic segment (Si), Ci is the total copy number (C) of Si, li is the length of Si, fik is the minor allele frequency of SNP k within Si, Mi is the copy number of a minor allele (M) at Si, and σri and σfi are noise parameters;
and
d) acquiring a value for mutation type, g, for which is indicative of the variant, being somatic, a subclonal somatic variant, germline, or not-distinguishable, wherein g, VAFI, p, C, and M are related to one another by the following:
VAFI
=
pM
+
g
⁡
(
1
-
p
)
pC
+
2
⁢
(
1
-
p
)
.

122 more elements

A system for characterizing a variant in a tumor sample as being a somatic or germline event from a subject, the system comprising:

at least one processor operatively connected to a memory, wherein the at least one processor when executing is configured to:
a) acquire:
i) a sequence coverage input (SCI), which comprises, for each of a plurality of selected subgenomic intervals, a value for sequence coverage at the selected subgenomic intervals, wherein SCI comprises a comparison of the number of reads for a subgenomic interval with the number of reads for a process-matched control, and wherein each of the plurality of selected subgenomic intervals is sequenced and the average sequence coverage prior to normalization is at least about 250×, and;
ii) an SNP allele frequency input (SAFI), which comprises, for each of a plurality of selected germline SNPs, a value for a minor allele frequency in the tumor sample, and wherein each of the plurality of selected germline SNPs is sequenced and the average sequence coverage prior to normalization is at least about 250×;
and
iii) a variant allele frequency input (VAFI), which comprises the allele frequency for said variant being characterized in the tumor sample, wherein the variant is sequenced and the average sequence coverage prior to normalization is at least about 250×;
b) acquire values, determined as a function of SCI and SAFI, for:
a genomic segment total copy number (C) for each of a plurality of genomic segments;
a genomic segment minor allele copy number (M) for each of the plurality of genomic segments;
and
sample purity (p),
wherein SCI, SAFI, C, M, and p are related to one another by the following:
r
ij
∼
N
(
log
2
⁢
p
*
C
i
+
(
1
-
p
)
*
2
p
*
(
∑
i
⁢
l
i
⁢
c
i
)
/
∑
i
⁢
l
i
+
(
1
-
p
)
*
2
,
σ
ri
,
and
⁢
⁢
fik
∼
N
⁡
(
p
*
Mi
+
(
1
-
p
)
*
1
p
*
Ci
+
(
1
-
p
)
*
2
,
σ
⁢
⁢
fi
)
,
when SCI and SAFI are noted as rij and fik, respectively;
and
where rij is the log ratio (LR) of subgenomic interval j within a genomic segment (Si), Ci is the total copy number (C) of Si, li is the length of Si, fik is the minor allele frequency of SNP k within Si, Mi is the copy number of a minor allele (M) at Si, and σri and σfi are noise parameters;
and
c) calculate a value for mutation type, g, which is indicative of the variant being somatic, germline, subclonal somatic, or not-distinguishable, wherein the at least one processor when executing is configured to calculate the value for mutation type, g, wherein g, VAFI, p, C, and M are related to one another by the following:
VAFI
=
pM
+
g
⁡
(
1
-
p
)
pC
+
2
⁢
(
1
-
p
)
.

122 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/274,525Filed 9 May 2014 · us provisional application
Priority: 10 May 2013
Published: US 2014/0336996 A113 Nov 2014
Granted: 17 Oct 2017
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

G16B 20/20
ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations: allele or variant detection, e.g. single…
G16B 20/00
Ict specially adapted for functional genomics or proteomics
G16B 20/10
ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations: ploidy or copy number detection
G16B
Bioinformatics, i.e. information and communication technology [ict] specially adapted for genetic or

Family

Application61/821,920Us provisional application · filed 10 May 2013
Application61/939,936Us provisional application · filed 14 Feb 2014
US 2014/0336996 A1Pre-grant publication · published 13 Nov 2014
US 9,792,403 B2This patent

From the US filing history. Foreign family members aren’t listed.

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A method of characterizing a variant in a tumor sample from a subject as being a somatic or germline event, the method comprising:

a) sequencing each of a plurality of selected subgenomic intervals, each of a plurality of selected germline SNPs, and a variant, wherein the average sequence coverage prior to normalization is at least about 250×;
b) acquiring:
i) a sequence coverage input (SCI), which comprises, for each of the plurality of selected subgenomic intervals, a value for normalized sequence coverage at the selected subgenomic intervals, wherein SCI comprises a comparison of the number of reads for a subgenomic interval with the number of reads for a process-matched control;
ii) an SNP allele frequency input (SAFI), which comprises, for each of the plurality of selected germline SNPs, a value for a minor allele frequency in the tumor sample;
and
iii) for said variant being characterized, a variant allele frequency input (VAFI), which comprises the allele frequency for said variant in the tumor sample;
c) acquiring values, as a function of SCI and SAFI, for:
a genomic segment total copy number (C) for each of a plurality of genomic segments;
a genomic segment minor allele copy number (M) for each of the plurality of genomic segments;
and
sample purity (p),
wherein SCI, SAFI, C, M, and p are related to one another by the following:
r
ij
∼
N
(
log
2
⁢
p
*
C
i
+
(
1
-
p
)
*
2
p
*
(
∑
i
⁢
l
i
⁢
c
i
)
/
∑
i
⁢
l
i
+
(
1
-
p
)
*
2
,
σ
ri
,
and
⁢
⁢
fik
∼
N
⁡
(
p
*
Mi
+
(
1
-
p
)
*
1
p
*
Ci
+
(
1
-
p
)
*
2
,
σ
⁢
⁢
fi
)
,
when SCI and SAFI are notated as rij and fik, respectively;
and
where rij is the log ratio (LR) of subgenomic interval j within a genomic segment (Si), Ci is the total copy number (C) of Si, li is the length of Si, fik is the minor allele frequency of SNP k within Si, Mi is the copy number of a minor allele (M) at Si, and σri and σfi are noise parameters;
and
d) acquiring a value for mutation type, g, for which is indicative of the variant, being somatic, a subclonal somatic variant, germline, or not-distinguishable, wherein g, VAFI, p, C, and M are related to one another by the following:
VAFI
=
pM
+
g
⁡
(
1
-
p
)
pC
+
2
⁢
(
1
-
p
)
.

122 more elements

Facts

Application

14/274,525Filed 9 May 2014 · us provisional application

Priority

10 May 2013

Published

US 2014/0336996 A113 Nov 2014

Granted

17 Oct 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

G16B 20/20
ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations: allele or variant detection, e.g. single…
G16B 20/00
Ict specially adapted for functional genomics or proteomics
G16B 20/10
ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations: ploidy or copy number detection
G16B
Bioinformatics, i.e. information and communication technology [ict] specially adapted for genetic or