Chronic Lymphocytic Leukemia (CLL) is a B-cell lymphoproliferative disorder primarily involving the bone marrow, blood and lymph nodes. CLL is the most common type of leukemia in adults and although median survival can be quite long, between 8-12 years, most eventually succumb to their disease. The evidence for a genetic component to CLL is compelling but remains unknown, and is likely complex. However, opportunities to identify underlying variants are apparent -both by varied and unique study and analysis designs and via collaborative efforts. The research plan we propose is multifaceted, highly collaborative and includes several innovative techniques. We will pursue two study designs, each powerful to identify susceptibility genes with different underlying genetic models: high-risk pedigree-based shared genomic segment analysis and case- control association analyses. Genome-wide shared genomic segment analysis is a new method that requires extremely extended, high-risk pedigrees which are available only to researchers with genealogic resources, such as Utah. Our strategy for association will be both genome wide and candidate region. Ascertainment will involve two sites (Utah and Sheffield, UK) and will include both a discordant family-based element (Utah) and a population-based sample (UK). This approach exploits both the increased power of familial cases with the perspective of population-based samples. We are able to pursue these together due to software that we have developed. In addition to conventional analyses, we will develop new methods for the high-risk pedigree and case-control settings: homozygosity mapping in the high-risk pedigrees and case-control SGS and homozygosity mapping. Both conventional and novel methods will be performed as part of broader collaborative efforts. The resource that we will build is timely. CLL genetic research is still in its infancy. The concurrent development of these designs defines an extensive strategy for identifying regions of the genome harboring CLL susceptibility genes and will afford us the opportunity to play a significant role in shaping the direction of CLL genetic research. Particularly, Utah pedigrees, through their structure and high-risk nature, add a previously unrealized aspect to the global picture. If one design or collaborative effort can identify even a single susceptibility gene for CLL, we will have made an important and critical discovery in the etiology of CLL. Such a discovery would not only help our understanding of the etiology of CLL, but also may provide information about other lymphoproliferative disorders and may translate to other cancers.

Public Health Relevance

This project is likely to lead to the identification of one or more genes predisposing to chronic lymphocytic leukemia (CLL). The individual public health implications are: the significantly increased accuracy that could be accomplished in risk estimation for CLL post-gene-identification and, in particular, identification of CLL precursors, insight into the overlapping genetic etiologies of CLL and other lymphoid neoplasms, and the potential improved ability for clinical decision making (for cases and gene carriers) based on genotype. The wider public health implications include the increased understanding that knowledge of any CLL predisposition gene will provide towards underlying the disease mechanism and direction towards the identification of additional predisposition genes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134674-04
Application #
8389597
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Caga-Anan, Emilie Charlisse F
Project Start
2009-12-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$504,949
Indirect Cost
$142,559
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Wang, Sophia S; Carrington, Mary; Berndt, Sonja I et al. (2018) HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes. Cancer Res 78:4086-4096
Wei, Xiaomu; Calvo-Vidal, M Nieves; Chen, Siwei et al. (2018) Germline Lysine-Specific Demethylase 1 (LSD1/KDM1A) Mutations Confer Susceptibility to Multiple Myeloma. Cancer Res 78:2747-2759
Waller, Rosalie G; Darlington, Todd M; Wei, Xiaomu et al. (2018) Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk. PLoS Genet 14:e1007111
Kleinstern, Geffen; Camp, Nicola J; Goldin, Lynn R et al. (2018) Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood 131:2541-2551
Law, Philip J; Berndt, Sonja I; Speedy, Helen E et al. (2017) Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia. Nat Commun 8:14175
Machiela, Mitchell J; Lan, Qing; Slager, Susan L et al. (2016) Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes. Hum Mol Genet 25:1663-76
Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F et al. (2016) Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia. Nat Commun 7:10933
Rand, Kristin A; Song, Chi; Dean, Eric et al. (2016) A Meta-analysis of Multiple Myeloma Risk Regions in African and European Ancestry Populations Identifies Putatively Functional Loci. Cancer Epidemiol Biomarkers Prev 25:1609-1618
Ziv, Elad; Dean, Eric; Hu, Donglei et al. (2015) Genome-wide association study identifies variants at 16p13 associated with survival in multiple myeloma patients. Nat Commun 6:7539
Coon, H; Darlington, T; Pimentel, R et al. (2013) Genetic risk factors in two Utah pedigrees at high risk for suicide. Transl Psychiatry 3:e325

Showing the most recent 10 out of 20 publications