Grant Details
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 |
Abstract
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.
Publications
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations
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
Related Citations