Genetic Susceptibility to Non-Hodgkin Lymphoma - Renewal: Dramatic increases worldwide in the incidence of non-Hodgkin lymphoma (NHL) have stimulated considerable efforts to identify factors that may aid in the prevention and treatment of this disease and to further our understanding of the biological mechanisms that initiate and sustain a lymphoid malignancy. As a continuation of grant R01 CA 104682-01, the overall goal of this proposal is to identify genetic variants that are causally related to risk of NHL using DNA from two large case-control studies based in the San Francisco Bay Area: SF Bay Area NHL1 (400 cases, 800 controls) and SF Bay Area NHL2 (1,800 cases, 1,800 controls). We have made considerable contributions to the field to date in identifying genetic risk factors of NHL in multiple studies. We have identified nearly thirty genes strongly associated with NHL during the previous grant period, from a recent genome scan and through collaborations within the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). These genes lie in the obesity, inflammation, hormone production and innate immunity pathways. Now, using the Illumina genotyping platform, under Aim#1, we will fine map these genes to identify true NHL risk alleles.
Under Aim#2, as part of ongoing replication studies within InterLymph, we will lead the fine mapping of genes associated with NHL based on a large pooled genetic study currently underway that is being spearheaded by Dr. Skibola. Using data from a recent genome scan, in Aim#3, we will assess the influence of copy number variation on risk of NHL, which will then be confirmed in our additional NHL cases and controls. Finally, we will test the function of putatively causal polymorphisms identified through Aims 1 and 2 and perform mechanistic studies of risk alleles to gain further insights that will enhance our current understanding of mechanisms involved in lymphomagenesis. Results from these studies 1) can be translated into prevention and treatment programs aimed at reducing the public health burden of NHL worldwide;2) use already existing DNA from two NHL case-control studies;3) use already existing data from our genome scan;4) will be the first to report genetic susceptibility of NHL based on copy number variation in population studies;and 5) will support major efforts to perform replication, fine mapping and pooled analyses within the InterLymph consortium.

Public Health Relevance

In 2008, non-Hodgkin lymphoma (NHL) will account for over 63,000 newly diagnosed cases and 20,000 associated deaths in the U.S. and over 300,000 cases and 172,000 deaths worldwide. Incidence and mortality rates have steadily increased over the last several decades, making NHL the fifth most common cancer in the U.S. An important role for family genetics has been established in causing lymphoma and common genetic variants may influence disease susceptibility. These studies will use genetics to increase our understanding of how lymphoma develops in the body and provide clues about environmental agents and lifestyle exposures that contribute to disease risk that may be translated to NHL screening, prevention and treatment programs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104682-08
Application #
8299618
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Mechanic, Leah E
Project Start
2003-09-30
Project End
2012-10-31
Budget Start
2012-08-01
Budget End
2012-10-31
Support Year
8
Fiscal Year
2012
Total Cost
$75,122
Indirect Cost
$25,553
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
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
Wang, Sophia S; Flowers, Christopher R; Kadin, Marshall E et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for peripheral T-cell lymphomas: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:66-75
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
Sille, F C M; Conde, L; Zhang, J et al. (2014) Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression. Genes Immun 15:133-6
Morton, Lindsay M; Sampson, Joshua N; Cerhan, James R et al. (2014) Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:1-14
Slager, Susan L; Benavente, Yolanda; Blair, Aaron et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:41-51
Skibola, Christine F; Slager, Susan L; Berndt, Sonja I et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for adult acute lymphocytic leukemia: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:125-9
Morton, Lindsay M; Slager, Susan L; Cerhan, James R et al. (2014) Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:130-44
Linet, Martha S; Vajdic, Claire M; Morton, Lindsay M et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for follicular lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:26-40
Aschebrook-Kilfoy, Briseis; Cocco, Pierluigi; La Vecchia, Carlo et al. (2014) Medical history, lifestyle, family history, and occupational risk factors for mycosis fungoides and S├ęzary syndrome: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr 2014:98-105

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