Molecular Epidemiology of AIDS-Lymphoma
Shehnaz Hussain, University of Calfornia Los Angeles
Basic Biomedical Sciences
Innovative, Developmental, Exploratory Award (IDEA)
AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) has recently surpassed Kaposi’s sarcoma as the most common AIDS-defining malignancy. The increased NHL burden appears to be a result of HIV-infected individuals living longer as a result of control for their opportunistic infections, but remaining vulnerable to AIDS-NHL due to dysfunctional immunity, specifically chronic B cell hyperactivation. Somatic mutation and repair of the immunoglobulin gene through two pathways, somatic hypermutation (SHM) and class switch recombination (CSR), is uncontrolled in an environment of chronic B cell hyperactivation and can result in mutations in oncogenes and proto-oncogenes and increased AIDS-NHL risk. The main hypothesis of this proposal is that adverse genotypes and haplotypes of genes involved in SHM and CSR, and high expression levels of AID (an enzyme that mutates DNA and initiates SHM and CSR), will pre-dispose to AIDS-NHL. To test this hypothesis, we will utilize the resources of two large prospective cohort studies of the natural and treated history of HIV and AIDS, the Multicenter AIDS Cohort Study (MACS) and the Women’s Interagency HIV Study (WIHS). The specific aims of this proposal are to 1) genotype 281 putatively functional and tagging SNPs in 30 candidate genes of SHM and CSR in 220 AIDS-NHL cases and 660 HIV+ matched controls and determine whether SNPs or haplotypes are associated with AIDS-NHL risk, and whether these associations are modified by epidemiological factors, HIV-progression related factors, tumor specific factors, molecular markers, and SNPs and haplotypes in other candidate genes, 2) quantify AID expression in PBMCs 1-3 years prior to AIDS-NHL diagnosis in 220 AIDS-NHL cases and at a matched time-point in 220 HIV+ controls and test for an association with AIDS-NHL risk, and 3) examine the association between SNPs and haplotypes in AICDA (the gene encoding AID) and AID expression in a sample of 220 HIV+ controls. This project will integrate high-throughput genotyping, innovative pathway-based statistical methods, and a wealth of previously prospectively collected clinical, epidemiological, and molecular information on cohort members, to explore a novel pathway in AIDS-NHL. The long-term goal of this proposed research is to elucidate the pathogenesis and molecular epidemiology of AIDS-NHL. In 2006, there were over 61,000 people in California living with AIDS who are at marked increased risk of NHL. This research has the potential to inform prevention, risk assessment, and early detection of NHL in HIV-infected populations in the future.