Genetic abnormalities in plasma cell dyscrasias

Abstract

Provided herein are non-invasive methods and biomarkers that identify progression and clonal evolution of plasma cell dyscrasias. Also provided are materials and methods for the diagnosis, prognosis, staging, and monitoring of plasma cell dyscrasias based on the presence of the biomarkers in a blood biopsy, as well as methods for monitoring the progression of a plasma cell dyscrasia, determining the efficacy of a therapeutic agent, determining a targeted therapy related to a plasma cell dyscrasia, and/or treating a plasma cell dyscrasia. The methods provided herein provide several advantages over invasive biopsies.

1 . A method comprising:
 determining that circulating free DNA (cfDNA), DNA from a circulating exosome (exoDNA), RNA from a circulating exosome (exoRNA), or DNA from a circulating tumor cell (CTC) from a blood biopsy from a human subject has one or more gene abnormalities;   wherein the one or more gene abnormalities comprises:   (i) a translocation selected from the group consisting of t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20);   (ii) a copy number variation (CNV) selected from the group consisting of a 1q21 amplification, a 1p32 deletion, a 13q deletion, a 16q deletion, and a 17p deletion; and   (iii) a single nucleotide variation (SNV) in a gene selected from the group consisting of CR1, DPY19L2, TMPRSS13, HBG1, KRAS, NRAS, BRAF, IRF4, MPEG1, RYR2, SLC24A1, FAT1, BCLAF1, CDC27, HLA-B, NBPF1, and ZFHX3.   
     
     
         2 . The method of  claim 1 , wherein the determining comprises analysis of all or part of an exome. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the one or more gene abnormalities comprises a translocation selected from the group consisting of t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). 
     
     
         6 . The method of  claim 1 , wherein the one or more gene abnormalities comprises a CNV selected from the group consisting of a 1q21 amplification, a 1p32 deletion, a 13q deletion, a 16q deletion, and a 17p deletion. 
     
     
         7 . The method of  claim 1 , wherein the one or more gene abnormalities comprises a SNV in a gene selected from the group consisting of CR1 DPY19L2, TMPRSS13, HBG1, KRAS, NRAS, BRAF, IRF4, MPEG1, RYR2, SLC24A1, FAT1, BCLAF1, CDC27, HLA-B, NBPF1, and ZFHX3. 
     
     
         8 . The method of  claim 7 , wherein the SNV is selected from the group consisting of CR1 (p.R2194*), CR1 (p.M2208T), DPY19L2 (p.I647V), TMPRSS13 (p.A77G), TMPRSS13 (p.Q78R), HBG1 (p.A137G), KRAS (p.G12D), KRAS (p.Q61H), NRAS (p.G12D), BRAF (p.G469R), IRF4 (p.L116R), MPEG1 (p.G537E), RYR2 (p.I784V), SLC24A1 (p.R686G), FAT1 (p.V3464I), FAT (p.K2895R), BCLAF1 (p.N629S), CDC27 (p.A273G), HLA-B (p.K210N), NBPF1 (p.D679E), NBPF1 (p.K41R), NBPF1 (p.L648V), ZFHX3 (p.Q2007*), ZFHX3 (p.H2001N), and ZFHX3 (p.F1800L). 
     
     
         9 .- 25 . (canceled) 
     
     
         26 . A method comprising:
 detecting in circulating free DNA (cfDNA), DNA from a circulating tumor cell (CTC), or DNA from a circulating exosome (exoDNA) or RNA from a circulating exosome (exoRNA) from a human subject one or more gene abnormalities;   wherein the one or more gene abnormalities comprises:   (i) a translocation selected from the group consisting of t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20);   (ii) a copy number variation (CNV) selected from the group consisting of a 1q21 amplification, a 1p32 deletion, a 13q deletion, a 16q deletion, and a 17p deletion; and   (iii) a single nucleotide variation (SNV) in a gene selected from the group consisting of CR1, DPY19L2, TMPRSS13, HBG1, KRAS, NRAS, BRAF, IRF4, MPEG1, RYR2, SLC24A1, FAT1, BCLAF1, CDC27, HLA-B, NBPF1, and ZFHX3, and   treating the human subject with a therapeutic agent for treatment of multiple myeloma.   
     
     
         27 .- 29 . (canceled) 
     
     
         30 . The method of  claim 26 , wherein the detecting comprises performing whole-exome sequencing and/or targeted deep sequencing of the cfDNA, the DNA from the CTC, the exoDNA, or the exoRNA. 
     
     
         31 .- 49 . (canceled) 
     
     
         50 . The method of  claim 26 , wherein the detecting comprises analysis of all or part of an exome. 
     
     
         51 . The method of  claim 26 , wherein the one or more gene abnormalities comprises a translocation selected from the group consisting of t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20). 
     
     
         52 . The method of  claim 26 , wherein the one or more gene abnormalities comprises a CNV selected from the group consisting of a 1q21 amplification, a 1p32 deletion, a 13q deletion, a 16q deletion, and a 17p deletion. 
     
     
         53 . The method of  claim 26 , wherein the one or more gene abnormalities comprises a SNV in a gene selected from the group consisting of CR1, DPY19L2, TMPRSS13, HBG1, KRAS, NRAS, BRAF, IRF4, MPEG1, RYR2, SLC24A1, FAT1, BCLAF1, CDC27, HLA-B, NBPF1, and ZFHX3. 
     
     
         54 . The method of  claim 53 , wherein the SNV is selected from the group consisting of CR1 (p.R2194*), CR1 (p.M2208T), DPY19L2 (p.I647V), TMPRSS13 (p.A77G), TMPRSS13 (p.Q78R), HBG1 (p.A137G), KRAS (p.G12D), KRAS (p.Q61H), NRAS (p.G12D), BRAF (p.G469R), IRF4 (p.L116R), MPEG1 (p.G537E), RYR2 (p.I784V), SLC24A1 (p.R686G), FAT1 (p.V3464I), FAT (p.K2895R), BCLAF1 (p.N629S), CDC27 (p.A273G), HLA-B (p.K210N), NBPF1 (p.D679E), NBPF1 (p.K41R), NBPF1 (p.L648V), ZFHX3 (p.Q2007*), ZFHX3 (p.H2001N), and ZFHX3 (p.F1800L). 
     
     
         55 . The method of  claim 26 , wherein the method comprises detecting in the cfDNA isolated from a blood biopsy from a human subject the one or more gene abnormalities. 
     
     
         56 . The method of  claim 26 , wherein the method comprises detecting in the exoDNA isolated from a blood biopsy from a human subject the one or more gene abnormalities. 
     
     
         57 . The method of  claim 26 , wherein the method comprises detecting in the exoRNA isolated from a blood biopsy from a human subject the one or more gene abnormalities. 
     
     
         58 . The method of  claim 26 , wherein the method comprises detecting in the DNA from a CTC isolated from a blood biopsy from a human subject the one or more gene abnormalities. 
     
     
         59 . The method of  claim 1 , wherein the determining comprises performing whole-exome sequencing and/or targeted deep sequencing of the cfDNA, the DNA from the CTC, the exoDNA, or the exoRNA. 
     
     
         60 . The method of  claim 1 , wherein the method comprises determining that the cfDNA isolated from a blood biopsy from a human subject has the one or more gene abnormalities. 
     
     
         61 . The method of  claim 1 , wherein the method comprises determining that the exoDNA isolated from a blood biopsy from a human subject has the one or more gene abnormalities. 
     
     
         62 . The method of  claim 1 , wherein the method comprises determining that the exoRNA isolated from a blood biopsy from a human subject has the one or more gene abnormalities. 
     
     
         63 . The method of  claim 1 , wherein the method comprises determining that the DNA from a CTC isolated from a blood biopsy from a human subject has the one or more gene abnormalities.