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The role of macrophages (Mo) and their prognostic impact in diffuse large B‐cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver‐X‐Receptors (LXRs) control Mo polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B‐cells, we found an intriguing association of NR1H3, encoding for the LXR‐α isoform, with the tumor microenvironment (TME). CIBERSORTx‐based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1‐like pro‐inflammatory Mo. By determining an expression cut‐off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on‐trial and real‐world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high‐resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo‐related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Summary: Relapsed or refractory diffuse large B‐cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico‐biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next‐generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety‐seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2‐microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R‐IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R‐IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R‐IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over‐representation of gene sets related to extra‐cellular matrix and tumour microenvironment. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors ( n = 132), MCL cell lines ( n = 6) and normal lymphoid tissue samples ( n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. [ABSTRACT FROM AUTHOR]

A recent genome wide association study of chronic lymphocytic leukaemia (CLL) provided evidence that common variation at 2q13 (rs17483466), 2q37.1 (rs13397985), 6p25.3 (rs872071), 11q24.1 (rs735665), 15q23 (rs7176508) and 19q13.32 (rs11083846) affects CLL risk. To verify and further explore the relationship between these variants and CLL risk we genotyped case-control datasets from Spain and Sweden (824 cases, 850 controls). Combined data provided statistically significant support for an association between genotypes at rs13397985, rs872071, rs735665, rs7176508 and rs11083846 and CLL risk. CLL risk increased with increasing numbers of risk alleles ( Ptrend = 1·40 × 10−15), consistent with a polygenic model of disease susceptibility. These data validate the relationship between common variation and risk of CLL. [ABSTRACT FROM AUTHOR]