Granted Patent
B1
US 12,595,518 · App. 18/905,647 · Granted Apr 7, 2026
Methods for assaying enriched nucleic acids
Inventors:
Charles M. Perou (Carrboro, NC); Joel S. Parker (Apex, NC); James Stephen Marron (Durham, NC); Andrew Nobel (Chapel Hill, NC); Philip S. Bernard (Salt Lake City, UT); Matthew J. Ellis (St. Louis, MO); Elaine Mardis (Troy, IL); Torsten O. Nielsen (Vancouver, CA); Maggie Chon U. Cheang (Vancouver, CA)
Assignees:
British Columbia Cancer Agency Branch; The University of North Carolina at Chapel Hill; University of Utah Research Foundation; Washington University
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Abstract
In an aspect, a method comprises providing a biological sample of a subject, and assaying nucleic acid molecules derived from RNA expression products of the biological sample to determine an RNA expression level of a plurality of genes, wherein the assaying comprises use of probes having sequences complementary to the nucleic acid molecules derived from the RNA expression products, to enrich the nucleic acid molecules for the plurality of genes.
Claims (34)
1 . A method comprising:
(a) providing a biological sample of a subject, and
(b) assaying nucleic acid molecules derived from RNA expression products of said biological sample to determine RNA expression levels corresponding to genes of said subject wherein said assaying comprises use of capture probes having sequences complementary to said nucleic acid molecules derived from said RNA expression products;
(c) generating a gene expression profile comprising RNA expression levels for a plurality of genes consisting of (i) 40 to 50 genes selected from ACTR3B, ANLN, BAG1, BCL2, BIRC5, BLVRA, CCNB1, CCNE1, CDC20, CDC6, CDCA1, CDH3, CENPF, CEP55, CXXC5, EGFR, ERBB2, ESR1, EXO1, FGFR4, FOXA1, FOXC1, GPR160, GRB7, HSPC150 (UBE2T), KIF2C, KNTC2, KRT14, KRT17, KRT5, MAPT, MDM2, MELK, MIA, MKI67, MLPH, MMP11, MYBL2, MYC, NAT1, ORC6L, PGR, PHGDH, PTTG1, RRM2, SFRP1, SLC39A6, TMEM45B, TYMS, and UBE2C and (ii) a set of housekeeping genes;
(d) comparing said gene expression profile to each of a set of centroids, wherein said set of centroids correspond to a plurality of breast cancer intrinsic subtypes; and
(e) assigning said biological sample to a breast cancer intrinsic subtype of said plurality of breast cancer intrinsic subtypes corresponding to a centroid among said set of centroids based at least upon a distance of said gene expression profile to said centroid.
2 . The method of claim 1 , wherein said subject has been diagnosed with cancer.
3 . The method of claim 2 , wherein said cancer is breast cancer.
4 . The method of claim 3 , wherein said biological sample is a breast tumor tissue sample.
5 . The method of claim 4 , wherein said breast tumor tissue sample is a formalin-fixed paraffin-embedded (FFPE) breast tumor tissue sample.
6 . The method of claim 1 , wherein said subject is undergoing a breast cancer therapy.
7 . The method of claim 6 , wherein said breast cancer therapy is an endocrine therapy.
8 . The method of claim 7 , wherein said endocrine therapy is a neoadjuvant endocrine therapy.
9 . The method of claim 6 , wherein said breast cancer therapy is a chemotherapy.
10 . The method of claim 1 , wherein said plurality of genes consists of
(i) 42 to 50 genes selected from ACTR3B, ANLN, BAG1, BCL2, BIRC5, BLVRA, CCNB1, CCNE1, CDC20, CDC6, CDCA1, CDH3, CENPF, CEP55, CXXC5, EGFR, ERBB2, ESR1, EXO1, FGFR4, FOXA1, FOXC1, GPR160, GRB7, HSPC150 (UBE2T), KIF2C, KNTC2, KRT14, KRT17, KRT5, MAPT, MDM2, MELK, MIA, MKI67, MLPH, MMP11, MYBL2, MYC, NAT1, ORC6L, PGR, PHGDH, PTTG1, RRM2, SFRP1, SLC39A6, TMEM45B, TYMS, and UBE2C and
(ii) a set of housekeeping genes.
11 . The method of claim 1 , wherein said plurality of genes consists of (i) 44 to 50 genes selected from ACTR3B, ANLN, BAG1, BCL2, BIRC5, BLVRA, CCNB1, CCNE1, CDC20, CDC6, CDCA1, CDH3, CENPF, CEP55, CXXC5, EGFR, ERBB2, ESR1, EXO1, FGFR4, FOXA1, FOXC1, GPR160, GRB7, HSPC150 (UBE2T), KIF2C, KNTC2, KRT14, KRT17, KRT5, MAPT, MDM2, MELK, MIA, MKI67, MLPH, MMP11, MYBL2, MYC, NAT1, ORC6L, PGR, PHGDH, PTTG1, RRM2, SFRP1, SLC39A6, TMEM45B, TYMS, and UBE2C and (ii) a set of housekeeping genes.
12 . The method of claim 1 , wherein said plurality of genes consists of (i) 46 to 50 genes selected from ACTR3B, ANLN, BAG1, BCL2, BIRC5, BLVRA, CCNB1, CCNE1, CDC20, CDC6, CDCA1, CDH3, CENPF, CEP55, CXXC5, EGFR, ERBB2, ESR1, EXO1, FGFR4, FOXA1, FOXC1, GPR160, GRB7, HSPC150 (UBE2T), KIF2C, KNTC2, KRT14, KRT17, KRT5, MAPT, MDM2, MELK, MIA, MKI67, MLPH, MMP11, MYBL2, MYC, NAT1, ORC6L, PGR, PHGDH, PTTG1, RRM2, SFRP1, SLC39A6, TMEM45B, TYMS, and UBE2C and (ii) a set of housekeeping genes.
13 . The method of claim 1 , wherein said plurality of genes consists of (i) 48 to 50 genes selected from ACTR3B, ANLN, BAG1, BCL2, BIRC5, BLVRA, CCNB1, CCNE1, CDC20, CDC6, CDCA1, CDH3, CENPF, CEP55, CXXC5, EGFR, ERBB2, ESR1, EXO1, FGFR4, FOXA1, FOXC1, GPR160, GRB7, HSPC150 (UBE2T), KIF2C, KNTC2, KRT14, KRT17, KRT5, MAPT, MDM2, MELK, MIA, MKI67, MLPH, MMP11, MYBL2, MYC, NAT1, ORC6L, PGR, PHGDH, PTTG1, RRM2, SFRP1, SLC39A6, TMEM45B, TYMS, and UBE2C and (ii) a set of housekeeping genes.
14 . The method of claim 1 , further comprising:
wherein said set of centroids is constructed at least in part by:
(1) detecting RNA expression levels of said plurality of genes in a plurality of training breast cancer samples that have been classified according to breast cancer intrinsic subtype, thereby generating a training gene expression profile, wherein each of the Luminal A (LumA), Luminal B (LumB), Basal-like (Basal), and HER2-enriched (HER2) breast cancer intrinsic subtypes is represented in the plurality of training breast cancer samples, and
(2) constructing centroids for each of said breast cancer intrinsic subtypes in said plurality of training breast cancer samples, at least in part by comparing, using a nearest centroid algorithm, said training gene expression profile of said training breast cancer samples to reference gene expression data.
15 . The method of claim 1 , further comprising predicting a response or a non-response to neoadjuvant therapy in the subject based at least in part on said assigning in (e), wherein said breast cancer intrinsic subtype assigned in (e) is indicative of said predicted response or non-response to said neoadjuvant therapy.
16 . The method of claim 15 , wherein said neoadjuvant therapy is neoadjuvant endocrine therapy, and wherein said biological sample is obtained from said subject after initiation of said neoadjuvant endocrine therapy.
17 . The method of claim 15 , further comprising predicting a response to said neoadjuvant therapy in said subject.
18 . The method of claim 17 , further comprising administering said neoadjuvant therapy to said subject responsive to said predicting.
19 . The method of claim 1 , wherein said RNA expression levels of said plurality of genes are normalized prior to said comparing in (d).
20 . The method of claim 19 , wherein said normalizing comprises normalization to said set of housekeeping genes.
21 . The method of claim 1 , wherein said set of housekeeping genes comprise a gene selected from the group consisting of MRPL19, PSMC4, SF3A1, PUM1, ACTB, GAPD, GUSB, RPLPO, and TFRC.
22 . The method of claim 1 , wherein the subject is node-negative.
23 . The method of claim 1 , wherein the subject is node-positive.
24 . The method of claim 1 , further comprising determining a likelihood of breast cancer recurrence of the subject.
Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 4, 2025
From: BERNARD, PHILIP S.
To: THE UNIVERSITY OF UTAH
Reel/Frame 070104/0761 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 4, 2025
From: ELLIS, MATTHEW; MARDIS, ELAINE
To: WASHINGTON UNIVERSITY
Reel/Frame 070104/0903 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 4, 2025
From: THE UNIVERSITY OF UTAH
To: UNIVERSITY OF UTAH RESEARCH FOUNDATION
Reel/Frame 070104/0900 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 4, 2025
From: PEROU, CHARLES M.; PARKER, JOEL S.; MARRON, JAMES STEPHEN; NOBEL, ANDREW
To: THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL
Reel/Frame 070104/0830 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Feb 4, 2025
From: NIELSEN, TORSTEN O.; CHEANG, MAGGIE
To: BRITISH COLUMBIA CANCER AGENCY BRANCH
Reel/Frame 070104/0757 →
Continuity (5)
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