Grant Number:	5R01CA235026-02 Interpret this number
Primary Investigator:	Slager, Susan
Organization:	Mayo Clinic Rochester
Project Title:	Integration of Germline and Tumor Genomes in Cll
Fiscal Year:	2020

Project Summary: Chronic lymphocytic leukemia (CLL) is a neoplasm of B-cell lymphocytes. It has a strong genetic component with 45 inherited single nucleotide polymorphisms (SNPs) identified through genome-wide association studies (GWAS). Using these SNPs, we computed a polygenic risk score (PRS), which is a weighted average of the risk alleles across the SNPs with the weights being the log odds ratios from SNP associations, and found that individuals in the upper quintile had a ~3-fold increased risk of CLL compared to the middle quintile (P<0.0001), providing evidence that the combination of known and common CLL susceptibility variants is one of the strongest CLL risk factors. In addition, whole genome and exome sequencing studies have recently identified over 60 recurrent somatic CLL variants or copy number alterations (CNA) and found that 88-90% of CLL cases have at least one putative driver mutation and ~44% have at least three driver mutations. However, little is known about how the inherited genetic variants interact with the tumor (at DNA and RNA level) and their contribution to tumor evolution. This application proposes to address this knowledge gap. In preliminary data from our CLL GWAS, we have evidence that a number of the CLL GWAS-discovered SNPs influence the expression levels of genes in cis (within 1-Mb window around the SNP) using RNA from whole blood or lymphoblastoid cell lines (LCL). However, because whole blood is a composition of multiple cell types, of which B-cells make up ~5-10%, B-cell specific signals are most likely missed, and gene expression from cell lines may be altered by the Epstein Barr Virus transformation used to generate LCL. Aim 1 proposes to overcome these limitations by using RNA from sorted tumor B-cells, sorted B-cells of healthy controls, and sorted clonal B-cells from individuals with the precursor condition to CLL, monoclonal B-cell lymphocytosis (MBL), to perform expression quantitative trait locus (eQTL) analyses. Validation and experimental in vitro studies will be performed to confirm and evaluate the functional relevance of variants of interest. Next, little is known about the extent of inherited germline variants in the individuals with somatic driver mutations. Aim 2 will address this gap to assess the relationship between germline and tumor DNA variants and to assess their effect on CLL outcomes. Finally, CLL is a heterogeneous disease with ~20% of CLL cases having a 5-year overall survival of 15-19%. There are a number of somatic variants that drive aggressive CLL disease, yet little is known about the role of inherited variants. Aim 3 will address this gap by identifying novel inherited variants associated with CLL aggressiveness. Upon completion, we will have identified gene targets of the known CLL susceptibility SNPs, will have characterized those CLL cases with high or low burden of genomic variants and assessed the effects on CLL outcomes, and will have gained insight into the genetic contribution to aggressive CLL. Our results may provide the potential discovery of novel biomarkers for targeted therapies, reveal novel ways to subclassify CLL, and develop potential genetic counseling strategies for family members.




Mosaic chromosomal alterations (mCAs) in individuals with monoclonal B-cell lymphocytosis (MBL).
Authors: Sekar A. , Griffin R. , Parikh S.A. , Genovese G. , Robinson D.P. , Norman A.D. , Olson J.E. , Rabe K.G. , Hoel M.S. , Boddicker N.J. , et al. .
Source: Blood Cancer Journal, 2024-11-06 00:00:00.0; 14(1), p. 193.
EPub date: 2024-11-06 00:00:00.0.
PMID: 39505849
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Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis (HCMBL).
Authors: Kleinstern G. , Boddicker N.J. , O'Brien D.R. , Allmer C. , Rabe K.G. , Norman A.D. , Griffin R. , Yan H. , Ma T. , Call T.G. , et al. .
Source: Blood Advances, 2024-02-15 00:00:00.0; , .
EPub date: 2024-02-15 00:00:00.0.
PMID: 38359367
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Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature.
Authors: Abdelbaky S. , Giacopelli B. , Rabe K.G. , Yamaguchi K. , Wu Y.Z. , Yan H. , Shanafelt T.D. , Parikh S.A. , Ding W. , Hampel P.J. , et al. .
Source: Blood, 2024-01-09 00:00:00.0; , .
EPub date: 2024-01-09 00:00:00.0.
PMID: 38194687
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Relationship among three common hematological premalignant conditions.
Authors: Boddicker N.J. , Parikh S.A. , Norman A.D. , Rabe K.G. , Griffin R. , Call T.G. , Robinson D.P. , Olson J.E. , Dispenzieri A. , Rajkumar V. , et al. .
Source: Leukemia, 2023-05-05 00:00:00.0; , .
EPub date: 2023-05-05 00:00:00.0.
PMID: 37147423
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Differential prognosis of single and multiple TP53 abnormalities in high count MBL and untreated CLL.
Authors: Griffin R. , Wiedmeier-Nutor J.E. , Parikh S.A. , McCabe C.E. , O'Brien D.R. , Boddicker N.J. , Kleinstern G. , Rabe K.G. , Bruins L. , Brown S. , et al. .
Source: Blood Advances, 2023-03-06 00:00:00.0; , .
EPub date: 2023-03-06 00:00:00.0.
PMID: 36877634
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The inherited genetic contribution and polygenic risk score for risk of CLL and MBL: a narrative review.
Authors: Kleinstern G. , Slager S.L. .
Source: Leukemia & Lymphoma, 2022-12-28 00:00:00.0; , p. 1-11.
EPub date: 2022-12-28 00:00:00.0.
PMID: 36576061
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Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.
Authors: Kleinstern G. , Weinberg J.B. , Parikh S.A. , Braggio E. , Achenbach S.J. , Robinson D.P. , Norman A.D. , Rabe K.G. , Boddicker N.J. , Vachon C.M. , et al. .
Source: Leukemia, 2022 Jan; 36(1), p. 119-125.
EPub date: 2021-07-20 00:00:00.0.
PMID: 34285341
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The CLL-international prognostic index (CLL-IPI) predicts outcomes in monoclonal B-cell lymphocytosis and Rai 0 CLL.
Authors: Parikh S.A. , Rabe K.G. , Kay N.E. , Call T.G. , Ding W. , Leis J.F. , Kenderian S.S. , Muchtar E. , Wang Y. , Koehler A. , et al. .
Source: Blood, 2021-04-19 00:00:00.0; , .
EPub date: 2021-04-19 00:00:00.0.
PMID: 33876228
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Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.
Authors: Macauda A. , Piredda C. , Clay-Gilmour A.I. , Sainz J. , Buda G. , Markiewicz M. , Barington T. , Ziv E. , Hildebrandt M.A.T. , Belachew A.A. , et al. .
Source: International Journal Of Cancer, 2021-03-06 00:00:00.0; , .
EPub date: 2021-03-06 00:00:00.0.
PMID: 33675538
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The humoral immune response to high-dose influenza vaccine in persons with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL).
Authors: Whitaker J.A. , Parikh S.A. , Shanafelt T.D. , Kay N.E. , Kennedy R.B. , Grill D.E. , Goergen K.M. , Call T.G. , Kendarian S.S. , Ding W. , et al. .
Source: Vaccine, 2021-02-12 00:00:00.0; 39(7), p. 1122-1130.
EPub date: 2021-01-16 00:00:00.0.
PMID: 33461835
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Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.
Authors: Kretzmer H. , Biran A. , Purroy N. , Lemvigh C. , Clement K. , Gruber M. , Gu H. , Rassenti L. , Mohammad A.W. , Lesnick C. , et al. .
Source: Blood Cancer Discovery, 2021 Jan; 2(1), p. 54-69.
EPub date: 2020-12-03 00:00:00.0.
PMID: 33604581
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Chronic lymphocytic leukemia (CLL) risk is mediated by multiple enhancer variants within CLL risk loci.
Authors: Yan H. , Tian S. , Kleinstern G. , Wang Z. , Lee J.H. , Boddicker N.J. , Cerhan J.R. , Kay N.E. , Braggio E. , Slager S.L. .
Source: Human Molecular Genetics, 2020-09-29 00:00:00.0; 29(16), p. 2761-2774.
PMID: 32744316
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Delineation of clinical and biological factors associated with cutaneous squamous cell carcinoma among patients with chronic lymphocytic leukemia.
Authors: Kleinstern G. , Rishi A. , Achenbach S.J. , Rabe K.G. , Kay N.E. , Shanafelt T.D. , Ding W. , Leis J.F. , Norman A.D. , Call T.G. , et al. .
Source: Journal Of The American Academy Of Dermatology, 2020-07-16 00:00:00.0; , .
EPub date: 2020-07-16 00:00:00.0.
PMID: 32682027
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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. .
Source: Blood Advances, 2020-06-23 00:00:00.0; 4(12), p. 2789-2797.
PMID: 32569378
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Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index.
Authors: Kleinstern G. , O'Brien D.R. , Li X. , Tian S. , Kabat B.F. , Rabe K.G. , Norman A.D. , Yan H. , Vachon C.M. , Boddicker N.J. , et al. .
Source: American Journal Of Hematology, 2020-04-12 00:00:00.0; , .
EPub date: 2020-04-12 00:00:00.0.
PMID: 32279347
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