Genome Wide-DNA Profiling of HIV-Related Non-Hodgkin Lymphomas: Implications for Disease Pathogenesis and Histogenesis.

Non-Hodgkin’s lymphomas (NHL) represent a frequent complication of HIV infection and a major source of morbidity and mortality amongst patients affected by acquired immunodeficiency syndrome. HIV-related NHL (HIV-NHL) are generally of B-cell origin and are phenotypically and histogenetically related to germinal center (GC) or post-GC B-cells. The pathogenesis of HIV-NHL is a multistep process involving factors provided by the host as well as alterations intrinsic to the tumor clone. Data on the underlying genetics of HIV-NHL are still scarce and mainly based on screening of genes known to be involved in the pathogenesis of lymphomas in an immunocompetent (IC) host. In order to elucidate the molecular pathogenesis of HIV-NHL, we performed a genome-wide DNA profiling based on microarray comparative genomic hybridization in 48 systemic HIV-NHL, including 28 HIV-diffuse large B-cell lymphomas (HIV-DLBCL), 13 HIV-Burkitt lymphomas (HIV-BL), and 7 HIV-Burkitt-like lymphomas (HIV-BLL), as well as in 4 HIV-primary central nervous system lymphoma (HIV-PCNSL) and in 2 HIV-primary effusion lymphomas (HIV-PEL). DNA samples, extracted from frozen biopsies, were analyzed using the Affymetrix Human Mapping 250K Nsp arrays. Aberrations occurring in 20% or more of the cases were defined as recurrent. HIV-DLBCL cases had recurrent gains at 2p15, 3q29, 4q13.2, 8p23.1, 10p12.31, 11q22.1–q24.1, 14q11.2, 14q32.33, 12p13.31-pter, 15q11.2, and recurrent losses at 1p36.32–p36.33, 2p11.2, 5p12, 3p14.2, 7q22.1, 8p23.1, 9p23, 9p24.1 12p11.1, 14q11.2, 15q11.2, 17p13.1–p13.3 and 22q11.1. In less than 20% of cases, gains of 1q, 8q, 21q and loss of 3q, 6q, 8p and 18q were also observed. Remarkably, there were no gains of 18q. HIV-BL had recurrent gains in 1q25.2, 3q29, 8p23.1, 15q11.2, 12p12.1-pter, 20q13.12 and recurrent losses at 15q11.2 and 17p11.2–p13.2. Regions of uniparental disomy longer than 5 Mb, were detected in 45% of the cases, including 7 (58%) HIV-BL, 10 (37%) HIV-DLBCL, 3/7 HIV-BLL and 2/2 HIV-PCNSL. One HIV-DLBCL and a cell line showed intragenic deletions of both the fragile histidine triad gene (FHIT), in the recurrently lost 3p14 region, and of the WW domain-containing oxidoreductase gene (WWOX), at 16q23.1, suggesting a synergistic effect of the loss of the two genes. Inactivation of FHIT gene by aberrant methylation of regulatory regions was investigated by methylation specific-PCR and was observed in 12 (25%) samples (8 HIV-DLBCL, 2 HIV-BL and 1 HIV-PCNSL), all with no 3p deletion. In conclusion, our data show a series of previously unreported recurrent aberrations in HIV-NHL. Also, HIV-BL show less copy number aberrations than HIV-DLBCL, and the pattern of gains and losses in HIV-DLBCL is more similar to the genetic profile observed in IC DLBCL derived from germinal center B-cells than that from activated B-cells (ABC). Finally, FHIT inactivation by DNA loss or promoter methylation, might have a pathogenetic role in at least 50% of HIV-NHL.