In-Depth Analysis Of Metabolic Phenotype By Studying Age- And Sex-Related Features Of Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is an age-related disease characterized by chronic hyperglycaemia mainly explained by insulin resistance and impaired insulin. T2DM is a worldwide increasing disease – in 2013, the International Diabetes Federation estimated that 382 million adults suffered from T2DM and that by 2035 there will be 592 people affected. These worrisome numbers challenge biomedical research at identifying new biomarkers for the diagnosis. The purpose of this study was to analyse and integrate different sources of clinical data with glycomics data in controls, prediabetics and diabetics cohorts, in order to 1) identify the major sources of variation in both data sets, 2) visualize patterns in variables within- and between-omics, 3) determine whether the identified patterns cluster according to known biological sources or conditions, and 5) estimate an aging clock based on the clinical variables and N-glycans and apply it to assess whether the groups of prediabetic and diabetic patients show an accelerated aging as compared with control and between sexes. The analytical methods employed were two-way partial least squares and regression. Results indicate that 1) the phenomics and glycomics joint components are different among groups and sexes over age, 2) intra- and inter-correlations between joint PCs obtained point to a common N-glycan signature (instead of endophenotype-specific), and 3) T2DM patients are biologically older than prediabetics and controls, being this effect more evident for male patients. Our main conclusions are that i) a combination of N-glycans could be used as complementary tool for the early diagnosis of metabolic dysregulation and/or T2D, ii) glycan peaks (GP) 1, GP2, and GP6 are confirmed as markers of aging, while GP8 and GP10 appear associated with dyslipidemia, and iii) this is the first time that prediabetics and diabetics have been included in an aging clock, as pure “healthy” controls do not exist

BCL3-rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

The t(14;19)(q32;q13) often juxtaposes BCL3 with IGH resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3-rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in CLL but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter 4 tumors transformed to a large B-cell lymphoma. We designed a novel FISH assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively

BCL3 rearrangements in B-cell lymphoid neoplasms occur in two breakpoint clusters associated with different diseases

The t(14;19)(q32;q13) often juxtaposes BCL3 with immunoglobulin heavy chain (IGH) resulting in overexpression of the gene. In contrast to other oncogenic translocations, BCL3 rearrangement (BCL3-R) has been associated with a broad spectrum of lymphoid neoplasms. Here we report an integrative whole-genome sequence, transcriptomic, and DNA methylation analysis of 13 lymphoid neoplasms with BCL3-R. The resolution of the breakpoints at single base-pair revealed that they occur in two clusters at 5' (n=9) and 3' (n=4) regions of BCL3 associated with two different biological and clinical entities. Both breakpoints were mediated by aberrant class switch recombination of the IGH locus. However, the 5' breakpoints (upstream) juxtaposed BCL3 next to an IGH enhancer leading to overexpression of the gene whereas the 3' breakpoints (downstream) positioned BCL3 outside the influence of the IGH and were not associated with its expression. Upstream BCL3-R tumors had unmutated IGHV, trisomy 12, and mutated genes frequently seen in chronic lymphocytic leukemia (CLL) but had an atypical CLL morphology, immunophenotype, DNA methylome, and expression profile that differ from conventional CLL. In contrast, downstream BCL3-R neoplasms were atypical splenic or nodal marginal zone lymphomas (MZL) with mutated IGHV, complex karyotypes and mutated genes typical of MZL. Two of the latter four tumors transformed to a large B-cell lymphoma. We designed a novel fluorescence in situ hybridization assay that recognizes the two different breakpoints and validated these findings in 17 independent tumors. Overall, upstream or downstream breakpoints of BCL3-R are mainly associated with two subtypes of lymphoid neoplasms with different (epi)genomic, expression, and clinicopathological features resembling atypical CLL and MZL, respectively