Grant Number:	1R01CA186646-01 Interpret this number
Primary Investigator:	Brown, Elizabeth
Organization:	University Of Alabama At Birmingham
Project Title:	Molecular Characterization of Myeloma and Related Asymptomatic Precursor States
Fiscal Year:	2014

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the 2nd most common hematologic malignancy accounting for ~1 percent of all cancers in the Western countries. Despite recent advances in treatment options, it remains incurable with high rates of relapse and drug resistance, with a median survival of ~5 years. Although the etiology of MM is unclear, it is preceded by precursor asymptomatic plasma cell dyscrasias known as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Despite the availability of clinical risk models, genomic aberrations and imaging, efforts to utilize these indices to accurately classify early stage precursor disease and monitor clinical course have not been successful. In contrast, recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of MM classification, and ultimately, management and treatment. The goal of the proposed investigation is to identify and characterize the contribution of miRNAs in serum exosomes on the presence of MM, and within the spectrum of progression, MGUS and SMM. We will test the overarching hypothesis that distinct serum exosome miRNAs will correlate with the presence of each precursor disease and myeloma phenotype and a subset of serum exosome miRNAs will correlate with the presence of all precursor disease and myeloma phenotypes relative to controls, giving rise to high priority targets important for MM risk. In addition, we hypothesize that miRNAs influence precursor disease and myeloma phenotypes by altering target gene expression. To address this hypothesis we intend to: (1) identify miRNAs associated with the presence of MM and its asymptomatic precursor states using discovery and independent replication populations and (2) characterize miRNA target genes important for the presence of MM and its asymptomatic precursor states using a whole transcriptome miRNA-mRNA approach. Direct modeling of miRNA-mRNA relationships is critical to advance our understanding of the role miRNAs in regulating post-transcriptional expression of target genes and in so doing, providing insight into biologic mechanism fundamental to disease etiology. This project leverages existing partnerships, resources and comprehensive, high quality clinical data and biospecimens collected in a network of populations to fill a critical gap in knowledge required to improve our understanding of myeloma etiology and disease states associated with progression. Such characterizations can be used to significantly transform the current paradigm for disease surveillance by advancing a set of biomarkers to target high-risk populations who may benefit from early detection and individualized clinical management.




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Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.
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Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.
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Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.
Authors: Clay-Gilmour A.I. , Hildebrandt M.A.T. , Brown E.E. , Hofmann J.N. , Spinelli J.J. , Giles G.G. , Cozen W. , Bhatti P. , Wu X. , Waller R.G. , et al. .
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Serum free light chain level at diagnosis in myeloma cast nephropathy-a multicentre study.
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Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.
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Heparanase promotes myeloma stemness and in vivo tumorigenesis.
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Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior.
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A Meta-analysis Of Multiple Myeloma Risk Regions In African And European Ancestry Populations Identifies Putatively Functional Loci
Authors: Rand K.A. , Song C. , Dean E. , Serie D.J. , Curtin K. , Sheng X. , Hu D. , Huff C.A. , Bernal-Mizrachi L. , Tomasson M.H. , et al. .
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Multiple Myeloma And Family History Of Lymphohaematopoietic Cancers: Results From The International Multiple Myeloma Consortium
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Fibronectin on the Surface of Myeloma Cell-derived Exosomes Mediates Exosome-Cell Interactions.
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A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium.
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Family history of hematologic malignancies and risk of multiple myeloma: differences by race and clinical features.
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