Skip to main content
An official website of the United States government
Grant Details

Grant Number: 5R01CA258924-03 Interpret this number
Primary Investigator: Brown, Jennifer
Organization: Dana-Farber Cancer Inst
Project Title: Genetic Predisposition to Chronic Lymphocytic Leukemia (CLL)
Fiscal Year: 2023


Abstract

Project Summary CLL is the most common leukemia of adults in North America, with about 20,000 new cases per year, and remains incurable. Although a small subset of patients has indolent disease, in the majority of cases CLL is characterized by steady progression toward therapy and once treated, patients are likely to die of the disease or its complications. The primary known risk factor is a family history of the disease, and CLL is one of the most heritable of all cancers, yet the genetic basis of this heritability remains largely unknown. Neither family-based linkage studies nor genomewide association studies (GWAS) have identified clinically useful genetic variants. In our prior work, we hypothesized that the high heritability of CLL may lie in rare germline variants associated with intermediate disease risks, and we identified ATM as the first risk gene for CLL. We further demonstrated that rare germline missense variants in ATM are associated with loss or mutation of the other allele in the tumor, as expected for a cancer predisposition gene. We have since identified these germline ATM variants in 25% of our CLL clinic population, suggesting that ATM may be an important germline driver of CLL. In this grant we will prospectively enroll CLL subjects who have been evaluated for germline ATM variants into a registry that will allow us to determine the association of ATM germline variants with CLL clinical features, development of other cancers and family history of cancer. We will also perform functional assessment of the ATM protein, to determine the impact of the most common and highest risk of these alleles on protein function. Additionally, we will expand the prior analysis that identified ATM, to include all publicly available CLL sequencing data, and employ both a novel highly sensitive variant calling method developed by Google and a novel ancestry matching method. Our preliminary data with this larger cohort and improved methodology have so far confirmed our ATM finding and identified FANCE and CHEK2 as additional CLL risk genes, suggesting a role for other DNA repair genes in CLL susceptibility. We will also focus on higher risk familial CLL with additional exome sequencing, with a similar analysis as above, and with epigenomic profiling with ATAC-seq to explore the non-coding genome. Using a unique cohort of highly impacted families, we will combine ATAC-seq with whole genome and RNA sequencing, to both characterize the gene targets of the GWAS alleles previously identified in CLL, and identify novel noncoding risk variants that impact transcription regulation. This project is feasible because of the rich resources of our unique, well-annotated tissue banks of familial CLL developed over the last 15 years. Our goal with this work is not only to enhance our understanding of the genetic basis of CLL, but also to provide the basis for improved screening and counseling of CLL patients in the clinic, through eventual initiation of clinical trials to assess the utility of genetic testing in this patient population.



Publications

Clinical Risks for Chronic Lymphocytic Leukemia.
Authors: Brown J.R. .
Source: Journal of the National Comprehensive Cancer Network : JNCCN, 2024 Apr; 22(3), .
PMID: 38626793
Related Citations

Optimization of Advanced Molecular Genetic Testing Utilization in Hematopathology: A Goldilocks Approach to Bone Marrow Testing.
Authors: AlJabban A. , Paik H. , Aster J.C. , Berliner N. , Brouillard J. , Brown J.R. , Burns K.H. , Castillo J.J. , Card J. , Dal Cin P. , et al. .
Source: JCO oncology practice, 2024 Feb; 20(2), p. 220-227.
EPub date: 2023-09-08.
PMID: 37683132
Related Citations

Mutations Detected in Real World Clinical Sequencing during BTK Inhibitor Treatment in CLL.
Authors: Brown J. , Mashima K. , Fernandes S. , Naeem A. , Shupe S. , Fardoun R. , Davids M. .
Source: Research square, 2024-01-16; , .
EPub date: 2024-01-16.
PMID: 38313250
Related Citations

Rare Germline ATM Variants Influence the Development of Chronic Lymphocytic Leukemia.
Authors: Lampson B.L. , Gupta A. , Tyekucheva S. , Mashima K. , Petráčková A. , Wang Z. , Wojciechowska N. , Shaughnessy C.J. , Baker P.O. , Fernandes S.M. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2023-02-10; 41(5), p. 1116-1128.
EPub date: 2022-10-31.
PMID: 36315919
Related Citations

Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia.
Authors: Kaufman M. , Yan X.J. , Li W. , Ghia E.M. , Langerak A.W. , Rassenti L.Z. , Belessi C. , Kay N.E. , Davi F. , Byrd J.C. , et al. .
Source: Frontiers in oncology, 2022; 12, p. 897280.
EPub date: 2022-07-12.
PMID: 35903706
Related Citations

Activation of Notch and Myc Signaling via B-cell-Restricted Depletion of Dnmt3a Generates a Consistent Murine Model of Chronic Lymphocytic Leukemia.
Authors: Biran A. , Yin S. , Kretzmer H. , Ten Hacken E. , Parvin S. , Lucas F. , Uduman M. , Gutierrez C. , Dangle N. , Billington L. , et al. .
Source: Cancer research, 2021-12-15; 81(24), p. 6117-6130.
EPub date: 2021-10-22.
PMID: 34686499
Related Citations

Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History.
Authors: Penter L. , Gohil S.H. , Lareau C. , Ludwig L.S. , Parry E.M. , Huang T. , Li S. , Zhang W. , Livitz D. , Leshchiner I. , et al. .
Source: Cancer discovery, 2021-12-01; 11(12), p. 3048-3063.
PMID: 34112698
Related Citations

Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study.
Authors: Davids M.S. , Lampson B.L. , Tyekucheva S. , Wang Z. , Lowney J.C. , Pazienza S. , Montegaard J. , Patterson V. , Weinstock M. , Crombie J.L. , et al. .
Source: The Lancet. Oncology, 2021 Oct; 22(10), p. 1391-1402.
EPub date: 2021-09-14.
PMID: 34534514
Related Citations

Post-Transformation IGHV-IGHD-IGHJ Mutations in Chronic Lymphocytic Leukemia B Cells: Implications for Mutational Mechanisms and Impact on Clinical Course.
Authors: Bagnara D. , Tang C. , Brown J.R. , Kasar S. , Fernandes S. , Colombo M. , Vergani S. , Mazzarello A.N. , Ghiotto F. , Bruno S. , et al. .
Source: Frontiers in oncology, 2021; 11, p. 640731.
EPub date: 2021-05-25.
PMID: 34113563
Related Citations

Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy.
Authors: Kretzmer H. , Biran A. , Purroy N. , Lemvigh C.K. , 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.
PMID: 33604581
Related Citations




Back to Top