Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and the number one hematological malignancy worldwide. NHL has a major impact on morbidity and mortality;thus, studies that lead to the identification of causal gene variants will help to identify at-risk individuals through better screening;provide important clues to identify biological pathways/targets that may be amenable to therapeutic modulation;and provide new directions for studies that benefit lymphoma research. To accomplish this, resequencing targeted genomic regions known to be associated with NHL based on genome-wide association studies, followed by validation of potentially causal SNPs in large, well-phenotyped studies (such as in a consortium) is of utmost importance and will help to establish true causal genetic variants. Further characterization of causal gene variants is also crucial. Based on findings from two GWAS of NHL, SNPs and HLA alleles on chromosome band 6p21.32-33 in the major histocompatibility complex (MHC) region were associated with risk of follicular lymphoma (FL), one of the major subtypes of NHL. Our GWAS suggests an important genetic role exists for FL. MHC regions have been previously linked to some autoimmune disorders suggesting that they may share common risk alleles with FL. InterLymph member studies have identified additional susceptibility loci, some outside of the MHC, that have been validated within the consortium. Thus, there is a strong impetus to identify causal gene variants known to affect risk of FL and other NHL subtypes since no studies of this kind for lymphoma have been performed. To accomplish this, the following Aims will be undertaken:
In Aim 1, targeted DNA capture and next generation sequencing will be implemented to identify all gene variants (rare and common SNPs and structural variants) in the MHC and in other regions associated with FL. The DNA has already been extracted from two large population-based case-control studies of NHL. Once novel and known SNPs are identified and tested for association with FL in the study populations, in silico functional analysis will be undertaken to predict causal SNPs.
In Aim 2, putatively functional SNPs will be genotyped in independent case-control studies within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph).
In Aim 3, HLA allelotypes and SNPs will be assessed in African-American FL cases to help address the issue of high LD in European populations within the MHC.
In Aim 4, validated SNPs will be functionally characterized. Accumulating evidence supports the role of genetic variation in the MHC with risk of many autoimmune diseases. Thus, the identification of causal gene variants in this region for lymphoma may also prove helpful in understanding other diseases sharing common susceptibility loci.

Public Health Relevance

Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S and will account for over 66,000 newly diagnosed cases and 20,000 deaths in the U.S. and 300,000 cases and 175,000 deaths worldwide in 2010. We will perform genetic studies that will aid in the identification of common genetic variants that cause lymphoma. These studies will increase our understanding of how lymphoma develops in the body and provide new ways to screen, prevent and treat lymphoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154643-02
Application #
8306082
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Mechanic, Leah E
Project Start
2011-07-22
Project End
2012-10-31
Budget Start
2012-05-01
Budget End
2012-10-31
Support Year
2
Fiscal Year
2012
Total Cost
$200,941
Indirect Cost
$63,572
Name
University of California Berkeley
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
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Cerhan, James R; Kricker, Anne; Paltiel, Ora et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:15-25
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Bracci, Paige M; Benavente, Yolanda; Turner, Jennifer J et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for marginal zone lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:52-65

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