Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

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Aim To assess the pathobiological and translational importance of whole blood transcriptomic analysis in inflammatory bowel disease (IBD). Methods We analyzed whole blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease [CD, n = 156], ulcerative colitis [UC, n = 167], and controls [n = 267]), exploring differential expression (DESeq2), co-expression networks (WGCNA), and transcription factor involvement (EPEE, ChEA, DoRothEA). Findings were validated by analysis of an independent replication cohort (99 CD, 100 UC, and 95 controls). In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD (8697 transcripts), CD (7152), and UC (8521), with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10 -118), MCEMP1 (LFC = 2.45, p = 7.37 × 10 -109), and S100A12 (LFC = 2.31, p = 2.15 × 10 -93). Significantly over-represented pathways included IL-1 (p = 1.58 × 10 -11), IL-4, and IL-13 (p = 8.96 × 10 -9). Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 (PU.1), CEBPB, and IRF2, all regulators of cytokine signaling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% CI 5.3–102.0). Conclusion Transcriptomic analysis has allowed for a detailed characterization of IBD pathobiology, with important potential translational implications.

In Norway, breast cancer survivors experience lower income than their cancer-free controls. This may indicate a need for financial compensations in order to maintain the standard of living for this group of patients.

considered to be a malignant lymphoma until immunostaining methods were applied. The nodular transformation of splenic red pulp in our three cases has not been seen without accompanying carcinomatous involvement. Therefore, it seems likely that this distinctive nodular pattern is caused by the infiltration of the metastatic tumour cells in the red pulp and accompanied by a desmoplastic stromal response. The degree of desmoplasia in the primary sites in our cases was generally low but the fibrosis of splenic red pulp was marked. The exact role of the tumour cells and of other factors in producing the nodular transformation of splenic red pulp is not established.We recently published a paper in which we reported a papillary carcinoma of the thyroid, which caused exuberant desmoplastic response within the thyroid and surrounding soft tissue resembling nodular fasciitis. The metastatic foci of the same carcinoma within the parathyroid gland and cervical lymph node grew without associated fasciitis-like stroma'. This case and the present cases suggest the importance of the microenvironment in the degree of desmoplasia that metastatic tumours can cause. References1. Harman JW. Dacorso P. Spread of carcinoma to the spleen. Arch. 2. Hirst AE. Bullock WK. Metastatic carcinoma of the spleen. Am. I. 3. Marymont JH. Gross S. Patterns of metastatic cancer in the spleen. 4. Berge T. Splenic metastases. Frequencies and patterns. APMIS [A] 5. Klein €3. Stein M. Kuten A et al. Splenomegaly and solilary spleen metastasis in solid tumors. Cancer 1987: 60; 100-102. 6. Michal M. Chlumska A, Fakan F. Papillary carcinoma of thyroid with exuberant nodular fasciitis-like stroma.