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US 2022/0178925 A1Published application
Multigene assay to assess risk of recurrence of cancer
AssigneeUniversity of Utah Research Foundation
InventorsKatherine (K-T) E. Varley, Rachel L. Stewart, Philip S. Bernard, Katherine Updike
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Abstract
Disclosed herein are biomarkers and methods of using the same for determining the risk of recurrence of cancer in a subject. The methods may include determining the level of expression of at least one MHCII gene, determining the level of expression of at least one TIL gene, and determining an Immune Activation Score for the subject. Further provided are methods of diagnosing a subject with triple-negative breast cancer (TNBC) as having TNBC Basal-like subtype, and methods of treating cancer in a subject.
Claims29
A method of determining the risk of recurrence of cancer in a subject, the method comprising:
- determining the level of expression in the subject of at least one Housekeeping gene selected from ACTB, MRPL19, RPLP0, PSMC4, and SF3A1;
- calculating a Housekeeping Score for the subject, which is the geometric mean of the expression levels of the Housekeeping genes;
- calculating a Normalization Factor for the subject, which is a Housekeeping Control divided by the Housekeeping Score for the subject;
- determining the level of expression in the subject of at least one WWII gene selected from CIITA, CD74, HLA-DPA1, HLA-DPB1, HLA-DPB2, HLA-DRB1, HLA-DMA, HLA-DMB, CTSH, and NCOA1;
- calculating a normalized expression level of each MHCII gene by multiplying the determined level of expression of each MHCII gene by the Normalization Factor for the subject;
- calculating a WWII Score for the subject, wherein the MHCII Score is the geometric mean of the normalized expression levels of the WWII genes;
- determining the level of expression in the subject of at least one TIL gene selected from CD3D, CD4, CD8A, CD69, IFNG, IL7R, PDCD1, CD274, and ARHGAP9;
- calculating a normalized expression level of each TIL gene by multiplying the determined level of expression of each TIL gene by the Normalization Factor for the subject;
- calculating a TIL Score for the subject, wherein the TIL Score is the geometric mean of the normalized expression levels of the TIL genes;
- determining an Immune Activation Score for the subject, wherein the Immune Activation Score is the geometric mean of the WWII Score and the TIL Score, and wherein the Immune Activation Score is calculated using the normalized expression levels of at least three genes from the set of TIL genes and WWII genes;
- and
- determining that the subject has an increased risk of cancer recurrence when the Immune Activation Score for the subject is less than a control Immune Activation Score, and that the subject has a decreased risk of cancer recurrence when the Immune Activation Score for the subject is greater than the control Immune Activation Score.
9 more elements
A method of diagnosing a subject with triple-negative breast cancer (TNBC) as having TNBC Basal-like subtype, the method comprising:
- determining the level of expression in the subject of at least one Housekeeping gene selected from ACTB, MRPL19, RPLP0, PSMC4, and SF3A1;
- calculating a Housekeeping Score for the subject, which is the geometric mean of the expression levels of the Housekeeping genes;
- calculating a Normalization Factor for the subject, which is a Housekeeping Control divided by the Housekeeping Score for the subject;
- determining the level of expression in the subject of at least one Basal-like gene selected from FOXC1, MKI67, CDC20, CCNE1, and ORC6;
- calculating a normalized expression level of each Basal-like gene by multiplying the determined level of expression of each Basal-like gene by the Normalization Factor for the subject;
- calculating a Basal-like Subtype Score for the subject, which is the geometric mean of the normalized expression levels of the Basal-like genes;
- determining that the subject has TNBC Basal-like subtype when the Basal-like Subtype Score for the subject is greater than or equal to a control Basal-like Subtype Score, and that the subject does not have TNBC Basal-like subtype when the Basal-like Subtype Score for the subject is less than the control Basal-like Subtype Score.
4 more elements
A method of diagnosing a subject with triple-negative breast cancer (TNBC) as having TNBC Basal-like subtype and determining the risk of recurrence of cancer in the subject, the method comprising:
- determining the level of expression in the subject of at least one Housekeeping gene selected from ACTB, MRPL19, RPLP0, PSMC4, and SF3A1;
- calculating a Housekeeping Score for the subject, which is the geometric mean of the expression levels of the Housekeeping genes;
- calculating a Normalization Factor for the subject, which is a Housekeeping Control divided by the Housekeeping Score for the subject;
- determining the level of expression in the subject of at least one Basal-like gene selected from FOXC1, MKI67, CDC20, CCNE1, and ORC6;
- calculating a normalized expression level of each Basal-like gene by multiplying the determined level of expression of each Basal-like gene by the Normalization Factor for the subject;
- calculating a Basal-like Subtype Score for the subject, which is the geometric mean of the normalized expression levels of the Basal-like genes;
- determining that the subject has TNBC Basal-like subtype when the Basal-like Subtype Score for the subject is greater than or equal to a control Basal-like Subtype Score, and that the subject does not have TNBC Basal-like subtype when the Basal-like Subtype Score for the subject is less than the control Basal-like Subtype Score;
- determining the level of expression in the subject of at least one WWII gene selected from CIITA, CD74, HLA-DPA1, HLA-DPB1, HLA-DPB2, HLA-DRB1, HLA-DMA, HLA-DMB, CTSH, and NCOA1;
- calculating a normalized expression level of each MHCII gene by multiplying the determined level of expression of each MHCII gene by the Normalization Factor for the subject;
- calculating a WWII Score for the subject, wherein the MHCII Score is the geometric mean of the normalized expression levels of the WWII genes;
- determining the level of expression in the subject of at least one TIL gene selected from CD3D, CD4, CD8A, CD69, IFNG, IL7R, PDCD1, CD274, and ARHGAP9;
- calculating a normalized expression level of each TIL gene by multiplying the determined level of expression of each TIL gene by the Normalization Factor for the subject;
- calculating a TIL Score for the subject, wherein the TIL Score is the geometric mean of the normalized expression levels of the TIL genes;
- determining an Immune Activation Score for the subject, wherein the Immune Activation Score is the geometric mean of the WWII Score and the TIL Score, and wherein the Immune Activation Score is calculated using the normalized expression levels of at least three genes from the set of TIL genes and WWII genes;
- and
- determining that the subject has an increased risk of cancer recurrence when the Immune Activation Score for the subject is less than a control Immune Activation Score, and that the subject has a decreased risk of cancer recurrence when the Immune Activation Score for the subject is greater than the control Immune Activation Score.
13 more elements
Dependencies are inferred from the claim text.