Grant Details
Grant Number: |
2R01CA073475-05A2 Interpret this number |
Primary Investigator: |
Martinez-Maza, Otoniel |
Organization: |
Children'S Hospital-La |
Project Title: |
Molecular Epidemiology of AIDS-Associated Lymphoma |
Fiscal Year: |
2002 |
Abstract
DESCRIPTION (Provided by the applicant): 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.
Publications
None