: Non-Hodgkin' s B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in HIV-infected people, not only in North America and Europe, but worldwide. In this proposal, studies are presented to elucidate the molecular epidemiology of AIDS-lymphoma. The proposed studies will utilize the resources of the Multicenter AIDS Cohort Study of the Natural History of AIDS (MACS). In prior studies supported by this award, elevated levels of various immune system molecules that are associated with B cell activation, including IL6 and IL10, sCD23, sCD27, sCD44, and IgE, were seen prior to the clinical detection of AIDS-lymphoma. Notably, there were clear differences in the patterns of expression of such B cell-stimulatory molecules seen in different subtypes of AIDS-lymphoma (Burkitt's/SNCCL vs. other subtypes), suggesting that there are differences in the character of the immune dysfunction that precedes the development of different subsets of these cancers. In addition to this, in very recent work we saw that a single-nucleotide polymorphism (SNP) in the IL10 promoter (-592 C/C), which is known to result in increased expression of IL10, was associated with the development of AIDS-lymphoma. These findings are of great significance, since few risk factors have been identified for AIDS-lymphoma.
The specific aims of the proposed studies are to determine: I ) if enhanced B cell stimulation, elevated immunoglobulin isotype switch activity, detectable c-myc:Ig gene translocations, and/or detectable circulating B cells with a germinal center-like phenotype, precede the development of AIDS- lymphoma, 2) if SNPs in the genes encoding B cell-stimulatory cytokines (IL6, IL10, TNFalpha, LTalpha, RANTES) are associated with an elevated risk for the development of AIDS-lymphoma, and 3) if subjects who have a genotype that has been seen to be associated with a decreased risk for developing AIDS-lymphoma (CCR5 delta-32 heterozygotes, SDF-1 3'UTR 801 G/G SNP, or IL10 promoter -592 A/A or A/C SNP) show lower levels of B cell activation. The accomplishment of these specific aims will add valuable new information to our understanding of the molecular epidemiology of AIDS-lymphoma, as well as the role of immune dysfunction in the generation and growth of this cancer. This information could form the foundation for future studies on the pathogenesis of AIDS-lymphoma, and may lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier and more effective clinical intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073475-06
Application #
6627777
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Starks, Vaurice
Project Start
1997-09-30
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
6
Fiscal Year
2003
Total Cost
$364,907
Indirect Cost
Name
University of California Los Angeles
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Breen, Elizabeth Crabb; Hussain, Shehnaz K; Magpantay, Larry et al. (2011) B-cell stimulatory cytokines and markers of immune activation are elevated several years prior to the diagnosis of systemic AIDS-associated non-Hodgkin B-cell lymphoma. Cancer Epidemiol Biomarkers Prev 20:1303-14
Regidor, Deborah L; Detels, Roger; Breen, Elizabeth C et al. (2011) Effect of highly active antiretroviral therapy on biomarkers of B-lymphocyte activation and inflammation. AIDS 25:303-14
Epeldegui, Marta; Vendrame, Elena; Martínez-Maza, Otoniel (2010) HIV-associated immune dysfunction and viral infection: role in the pathogenesis of AIDS-related lymphoma. Immunol Res 48:72-83
Wong, Hui-Lee; Breen, Elizabeth C; Pfeiffer, Ruth M et al. (2010) Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study. AIDS 24:1025-33
Widney, Daniel P; Gui, Dorina; Popoviciu, Laura M et al. (2010) Expression and Function of the Chemokine, CXCL13, and Its Receptor, CXCR5, in Aids-Associated Non-Hodgkin's Lymphoma. AIDS Res Treat 2010:164586
Aissani, Brahim; Ogwaro, Kisani M; Shrestha, Sadeep et al. (2009) The major histocompatibility complex conserved extended haplotype 8.1 in AIDS-related non-Hodgkin lymphoma. J Acquir Immune Defic Syndr 52:170-9
Cozen, W; Cerhan, J R; Martinez-Maza, O et al. (2007) The effect of atopy, childhood crowding, and other immune-related factors on non-Hodgkin lymphoma risk. Cancer Causes Control 18:821-31
Epeldegui, Marta; Breen, Elizabeth Crabb; Hung, Yee Ping et al. (2007) Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis. AIDS 21:2265-70
Epeldegui, Marta; Hung, Yee Ping; McQuay, Amy et al. (2007) Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations. Mol Immunol 44:934-42
Breen, Elizabeth Crabb; Fatahi, Sepi; Epeldegui, Marta et al. (2006) Elevated serum soluble CD30 precedes the development of AIDS-associated non-Hodgkin's B cell lymphoma. Tumour Biol 27:187-94

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