Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

PMCID: PMC3544714This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

CALING (Corpus de Accesibilidad Lingüística) Corpus : accessibility and real informants evaluation

There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a 'fusion gene'. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies

Ants of Bimini

16 p. ; 24 cm.Includes bibliographical references (p. 14-16)

Patient empowerment, eating behaviours and illness control: pre-post outcomes from DWELL delivery in UK and France

Diabetes self-management programmes can improve clinical and healthy lifestyle outcomes. Research has demonstrated that improved engagement with type 2 diabetes (T2D) care is associated with greater empowerment beliefs and a perceived internal control over their illness. As part of the DWELL evaluation study, an interim subset of 139 participants in the UK and 53 participants in France were assessed pre- and post-intervention on measures of weight, BMI, waist circumference and glycated haemoglobin (HbA1c), as well as self-efficacy beliefs (DES-SF), healthy eating behaviours (DEBQ) and perceptions of illness (IPQ-R). Pre-post comparisons in both countries demonstrated statistically significant decreases in weight (UK: Z = 6.71, p<.001, FR: Z = 3.33, p<.05), BMI (UK: Z = 6.70, p<.001, FR: Z = 3.21, p<.05), waist circumference (UK: Z = 6.71, p<.001, FR: Z = 3.24, p<.05) ,and HbA1c (UK: Z = 6.29, p<.001, FR: Z = 4.18, p <.001). Importantly, participation in the DWELL programme was associated with increased self-efficacy beliefs (UK: Z = 5.63, p<.001, FR: Z = 5.54, p<.001), greater perceived personal control over their diabetes (UK: Z = 3.17, p<.05, FR: Z = 2.20, p<.05), reduced negative feelings about their illness (UK: Z = 3.01, p <.05, FR: Z = 2.19, p<.05) and decreased eating in response to external food cues (UK: Z = 3.79, p<.001, FR: Z = 2.34, p<.05). In the UK, participants also reported an increased optimism for treatment control of their diabetes (Z = 3.06, p <.05) and for their long-term prognosis (Z = 1.99, p<.05). These preliminary findings support the efficacy of the DWELL programme in improving diabetes-related biomedical outcomes, as well as improvements in patient empowerment, healthy eating habits and increased perceived illness control. Further analysis, available at a later date, will include a larger sample of participants, including longitudinal data with follow-ups six- and 12- months post participation in the DWELL programme

Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series

Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block. Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel functional roles for genes determining tissue-specific metabolism

Conserved properties of genetic architecture of renal and fat transcriptomes in rat models of insulin resistance

To define renal molecular mechanisms that are affected by permanent hyperglycemia and may promote phenotypes relevant to diabetes nephropathy, we carried out linkage analysis of genome-wide gene transcription in kidney of F2 offspring from the Goto-Kakizaki (GK) rat model of type 2 diabetes and normoglycemic Brown Norway (BN) rats. We mapped 2526 statistically significant expression quantitative trait loci (eQTLs) in the cross. Over 40% of eQTLs mapped in the close vicinity of the linked transcripts, underlying possible cisregulatory mechanisms of gene expression. We identified eQTL hotspots on chromosomes 5 and 9 regulating the expression of 80-165 genes, sex or cross direction effects, and enriched metabolic and immunological processes by segregating GK alleles. Comparative analysis with adipose tissue eQTLs in the same cross showed that 496 eQTLs, as well as top enriched biological pathways, are conserved in the two tissues. Extensive similarities in eQTLs mapped in the GK and in the spontaneously hypertensive rat (SHR) suggest a common etiology of disease phenotypes common to the two strains, including insulin resistance which is a prominent pathophysiological feature in both GK and SHR. Our data shed light on shared and tissue specific molecular mechanisms that may underlie etiological aspects of insulin resistance in the contexts of spontaneously occurring hyperglycemia and hypertension

Combined exome and transcriptome sequencing of non-muscle-invasive bladder cancer: associations between genomic changes, expression subtypes, and clinical outcomes.

BACKGROUND: Three-quarters of bladder cancer patients present with early-stage disease (non-muscle-invasive bladder cancer, NMIBC, UICC TNM stages Ta, T1 and Tis); however, most next-generation sequencing studies to date have concentrated on later-stage disease (muscle-invasive BC, stages T2+). We used exome and transcriptome sequencing to comprehensively characterise NMIBCs of all grades and stages to identify prognostic genes and pathways that could facilitate treatment decisions. Tumour grading is based upon microscopy and cellular appearances (grade 1 BCs are less aggressive, and grade 3 BCs are most aggressive), and we chose to also focus on the most clinically complex NMIBC subgroup, those patients with grade 3 pathological stage T1 (G3 pT1) disease. METHODS: Whole-exome and RNA sequencing were performed in total on 96 primary NMIBCs including 22 G1 pTa, 14 G3 pTa and 53 G3 pT1s, with both exome and RNA sequencing data generated from 75 of these individual samples. Associations between genomic alterations, expression profiles and progression-free survival (PFS) were investigated. RESULTS: NMIBCs clustered into 3 expression subtypes with different somatic alteration characteristics. Amplifications of ARNT and ERBB2 were significant indicators of worse PFS across all NMIBCs. High APOBEC mutagenesis and high tumour mutation burden were both potential indicators of better PFS in G3pT1 NMIBCs. The expression of individual genes was not prognostic in BCG-treated G3pT1 NMIBCs; however, downregulated interferon-alpha and gamma response pathways were significantly associated with worse PFS (adjusted p-value < 0.005). CONCLUSIONS: Multi-omic data may facilitate better prognostication and selection of therapeutic interventions in patients with G3pT1 NMIBC. These findings demonstrate the potential for improving the management of high-risk NMIBC patients and warrant further prospective validation