ABSTRACT
Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
Subject(s)
Lymphoma, B-Cell, Marginal Zone , Splenic Neoplasms , Aged , Animals , Female , Humans , Male , Mice , Middle Aged , Chromosome Aberrations , Immunophenotyping , Lymphoma, B-Cell, Marginal Zone/diagnosis , Lymphoma, B-Cell, Marginal Zone/genetics , Multigene Family , Mutation , Spleen/pathology , Splenic Neoplasms/diagnosis , Splenic Neoplasms/genetics , Transcriptome , Tumor MicroenvironmentABSTRACT
OBJECTIVES: Immune activation, among others driven by interferon (IFN)-α and IFN-γ activation, is a main feature of progressive HIV infection. Suppressor of cytokine signaling (SOCS) 1 and 3 are negative feedback regulators of the IFN-α and IFN-γ axis. Here, we analyzed the role of 9 single-nucleotide polymorphisms (SNPs) within SOCS-1 and SOCS-3 genes for their association with an HIV progression rate in a cohort of 318 rapid vs 376 slow progressors from the Swiss HIV Cohort Study. DESIGN AND METHODS: We analyzed 9 SNPs, which we have identified in Swiss blood donors, in a cohort of HIV-infected patients (n = 1144), which have been categorized according to the decline in CD4 T-cell counts. In all the conducted analyses, we focused on the comparison between rapid and slow progressors with regard to SNPs in SOCS-1 and SOCS-3 and with regard to haplotypes using multivariate logistic regression models. RESULTS: Three SOCS-1 SNPs (rs193779, rs33989964, and rs4780355) are associated with a risk reduction for rapid progression. Two of these SNPs, rs33989964 and rs4780355, are in strong linkage disequilibrium, forming a frequent haplotype. Homozygous carriers of this haplotype are also associated with a risk reduction for rapid progression. By contrast, the minor TT genotype of rs33977706 is associated with twice the risk for rapid progression. No associations have been observed for the 4 SOCS-3 SNPs or the major SOCS-3 haplotypes. CONCLUSIONS: Our data suggest that SNPs in SOCS-1 are associated with HIV disease progression and speak in favor that immune activation is causal for the progressive immunodeficiency.
