Diagnosis, prognosis and identification of potential therapeutic targets of multiple myeloma based on gene expression profiling

• US 20080293578A1
• Filed: 02/01/2008
• Published: 11/27/2008
• Est. Priority Date: 11/07/2001
• Status: Active Grant

• Current Assignee: Bioventures, LLC
• Original Assignee: Bart Barlogie, Fenghuang Zhan, John D. Shaugnessy
• Inventors: Zhan, Fenghuang, Barlogie, Bart, Shaugnessy, John D.
• Granted Patent: US 7,983,850 B2
• Time in Patent Office: Days
• US Class Current: 506/3
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12Q 1/6837 using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/112 Disease subtyping, staging or classification
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Provided herein is a method for gene expression profiling multiple myeloma patients into distinct subgroups via DNA hybridization and hierarchical clustering analysis of the hybridization data where the results may further be used to identify therapeutic gene targets. Also provided is a method for controlling bone loss in an individual via pharmacological inhibitors of DKK1 protein. In addition provided herein is a method for diagnosing multiple myeloma using a 15-gene model that classifies myeloma into groups 1-7.

Claims

1. A method of gene expression profiling for multiple myeloma, comprising:

isolating plasma cells from individuals with or without multiple myeloma;

isolating nucleic acid samples from said plasma cells;

hybridizing said nucleic acid samples to a DNA microarray;

performing hierarchical clustering analysis on data obtained from said hybridization, wherein the clustering analysis classifies the individuals with or without multiple myeloma into distinct subgroups MM1, MM2, MM3, and MM4.

2. The method of claim 1, further comprising:

identifying genes with significantly different levels of expression in multiple myeloma patients as compared to normal individuals after the cluster analysis, wherein said genes are potential therapeutic targets for multiple myeloma.

3. The method of claim 2, wherein said potential therapeutic targets for multiple myeloma are genes with accession numbers L36033, M63928, U64998, M20902, M26602, M21119, M14636, M26311, M54992, X16832, M12529, M15395, Z74616, HT2152, U97105, U81787, HT3165, M83667, L33930, D83657, M11313, M31158, U24577, M16279, HT2811, M26167, U44111, X59871, X67235, U19713, Y08136, M97676, M64590, M20203, M30257, M93221, S75256, U97188, Z23091, M34344, M25897, M31994, Z31690, S80267, U00921, U09579, U78525, HT5158, X57129, M55210, L77886, U73167, X16416, U57316, Y09022, M25077, AC002115, Y07707, L22005, X66899, D50912, HT4824, U10324, AD000684, U68723, X16323, U24183, D13645, S85655, X73478, L77701, U20657, M59916, D16688, X90392, U07424, X54199, L06175, M55267, M87507, M90356, U35637, L06845, U81001, U76189, U53225, X04366, U77456, L42379, U09578, Z80780, HT4899, M74088, X57985, X79882, X77383, M91592, X63692, M60752, M96684, U16660, M86737, U35113, X81788, HT2217, M62324, U09367, X89985, L19871, X69398, X05323, X04741, D87683, D17525, M64347, U89922, X67325, X59798, U62800, U35340, X12530, X59766, U58096, U52513, X76223, X92689, D17427, L11329, L13210, U10991, L10373, U60873, M65292, HT4215, D13168, AC002077, M92934, X82494, M30703, U9103, or NM012242.

4. A method of controlling bone loss in an individual, comprising:

administering to the individual a pharmacological inhibitor of DKK1 protein.

5. The method of claim 4, wherein the individual has multiple myeloma, osteoporosis, post-menopausal osteoporosis, or malignancy-related bone loss.

6. The method of claim 5, wherein the malignancy-related bone loss is caused by breast cancer metastasis to the bone or prostate cancer metastasis to the bone.

7. A method for diagnosis of multiple myeloma, comprising the steps of:

(a) isolating biological samples from an individual;

(b) examining the expression levels of a group of genes comprising CCND1, MAF, MAFB, FGFR3, and MMSET or determining chromosomal translocation represented by overexpression of a group of genes comprising CCND1, MAF, MAFB, FGFR3, and MMSET; and

(c) examining the expression levels of a group of genes comprising CST6, RAB7L1, MAP4K3, HRASLS2, TRAIL, IG, FGL2, GNG11, MCM2 and FLJ10709, wherein results from steps (b) and (c) classify the individual into one of multiple myeloma groups 1-7.

8. The method of claim 7, wherein the biological samples are plasma cells.

9. The method of claim 7, wherein individual in myeloma groups 1, 2, 3 and 6 have a poor prognosis compared to an individual in myeloma groups 4, 5 and 7.

10. The method of claim 7, wherein overexpression of CCND1 or translocation t(11;

14)(q13;

q32) classifies the individual into myeloma group 3.

11. The method of claim 7, wherein overexpression of MAF or MAFB, or translocation t(14;

16)(32;

q23) or t(14;

20)(q32;

q13) classifies the individual into myeloma group 5.

12. The method of claim 7, wherein overexpression of FGFR3 or MMSET or translocation t(4;

14)(p21;

q32) classifies the individual into myeloma group 7.

13. The method of claim 7, wherein overexpression of CST6, RAB7L1, MAP4K3, and HRASLS2 and downregulation of TRAIL classify the individual into myeloma group 6.

14. The method of claim 7, wherein downregulation of CST6, RAB7L1, MAP4K3, HRASLS2, GNG11, MCM2, and FLJ10709 and overexpression of TRAIL, IG and FGFL2 classify the individual into myeloma group 1.

15. The method of claim 7, wherein downregulation of CST6, RAB7L1, MAP4K3, HRASLS2, IG, FGFL2, MCM2, and FLJ10709 and overexpression of TRAIL and GNG11 classify the individual into myeloma group 2.

16. The method of claim 7, wherein downregulation of CST6, RAB7L1, MAP4K3, HRASLS2, IG, FGFL2, and GNG11 and overexpression of TRAIL, MCM2 and FGFL2 classify the individual into myeloma group 4.