Exome-wide somatic mutation characterization of small bowel adenocarcinoma

Small bowel adenocarcinoma (SBA) is an aggressive disease with limited treatment options. Despite previous studies, its molecular genetic background has remained somewhat elusive. To comprehensively characterize the mutational landscape of this tumor type, and to identify possible targets of treatment, we conducted the first large exome sequencing study on a population-based set of SBA samples from all three small bowel segments. Archival tissue from 106 primary tumors with appropriate clinical information were available for exome sequencing from a patient series consisting of a majority of confirmed SBA cases diagnosed in Finland between the years 2003-2011. Paired-end exome sequencing was performed using Illumina HiSeq 4000, and OncodriveFML was used to identify driver genes from the exome data. We also defined frequently affected cancer signalling pathways and performed the first extensive allelic imbalance (Al) analysis in SBA. Exome data analysis revealed significantly mutated genes previously linked to SBA (TP53, KRAS, APC, SMAD4, and BRAF), recently reported potential driver genes (SOX9, ATM, and ARID2), as well as novel candidate driver genes, such as ACVR2A, ACVR1B, BRCA2, and SMARCA4. We also identified clear mutation hotspot patterns in ERBB2 and BRAF. No BRAF V600E mutations were observed. Additionally, we present a comprehensive mutation signature analysis of SBA, highlighting established signatures 1A, 6, and 17, as well as U2 which is a previously unvalidated signature. Finally, comparison of the three small bowel segments revealed differences in tumor characteristics. This comprehensive work unveils the mutational landscape and most frequently affected genes and pathways in SBA, providing potential therapeutic targets, and novel and more thorough insights into the genetic background of this tumor type.Peer reviewe

APOBEC mutagenesis is a common process in normal human small intestine

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA. Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.Peer reviewe

Comprehensive evaluation of coding region point mutations in microsatellite-unstable colorectal cancer

Microsatellite instability (MSI) leads to accumulation of an excessive number of mutations in the genome, mostly small insertions and deletions. MSI colorectal cancers (CRCs), however, also contain more point mutations than microsatellite-stable (MSS) tumors, yet they have not been as comprehensively studied. To identify candidate driver genes affected by point mutations in MSI CRC, we ranked genes based on mutation significance while correcting for replication timing and gene expression utilizing an algorithm, MutSigCV. Somatic point mutation data from the exome kit-targeted area from 24 exome-sequenced sporadic MSI CRCs and respective normals, and 12 whole-genome-sequenced sporadic MSI CRCs and respective normals were utilized. The top 73 genes were validated in 93 additional MSI CRCs. The MutSigCV ranking identified several well-established MSI CRC driver genes and provided additional evidence for previously proposed CRC candidate genes as well as shortlisted genes that have to our knowledge not been linked to CRC before. Two genes, SMARCB1 and STK38L, were also functionally scrutinized, providing evidence of a tumorigenic role, for SMARCB1 mutations in particular. © 2018 The Authors. Published under the terms of the CC BY 4.0 licensePeer reviewe

When TADs go bad: chromatin structure and nuclear organisation in human disease

Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.Peer reviewe

The Glanville fritillary genome retains ancient karyotype and reveals selective chromosomal fusions in Lepidoptera

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Adhesion of perfume-filled microcapsules to model fabric surfaces

The retention and adhesion of melamine formaldehyde (MF) microcapsules on a model fabric surface in aqueous solution were investigated using a customised flow chamber technique and atomic force microscopy (AFM). A cellulose film was employed as a model fabric surface. Modification of the cellulose with chitosan was found to increase the retention and adhesion of microcapsules on the model fabric surface. The AFM force–displacement data reveal that bridging forces resulting from the extension of cellulose chains dominate the adhesion between the microcapsule and the unmodified cellulose film, whereas electrostatic attraction helps the microcapsules adhere to the chitosan-modified cellulose film. The correlation between results obtained using these two complementary techniques suggests that the flow chamber device can be potentially used for rapid screening of the effect of chemical modification on the adhesion of microparticles to surfaces, reducing the time required to achieve an optimal formulation

Autoimmunity, hypogammaglobulinemia, lymphoproliferation and mycobacterial disease in patients with dominant activating mutations in STAT3

The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of IPEX-like syndrome. Here, we immunologically characterized three patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T and p.K658N, respectively). The patients displayed multi-organ autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4-CD8-) T cells, and decreased NK, Th17, and regulatory T cell numbers. Notably, the patient harboring the K392R mutation developed T cell LGL leukemia at age 14. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity.</p