Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

High-throughput transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium abscessus Smooth and Rough variants

BACKGROUND: Mycobacterium abscessus (MAB) is an emerging pathogen causing pulmonary infections in those with inflammatory lung disorders, such as Cystic Fibrosis (CF), and is associated with the highest fatality rate among rapidly growing mycobacteria (RGM). Phenotypically, MAB manifests as either a Smooth (MAB-S) or a Rough (MAB-R) morphotype, which differ in their levels of cell wall glycopeptidolipids (GPLs) and in their pathogenicity in vivo. As one of the primary immune cells encountered by MAB, we sought to examine the early transcriptional events within macrophages, following infection with both MAB-S or MAB-R. RESULTS: We sampled the transcriptomes (mRNA and miRNA) of THP-1-derived macrophages infected with both MAB-R and MAB-S at 1, 4 and 24 h post-infection (hpi) using RNA-seq. A core set of 606 genes showed consistent expression profiles in response to both morphotypes, corresponding to the early transcriptional response to MAB. The core response is type I Interferon (IFN)-driven, involving the NF-κB and MAPK signaling pathways with concomitant pro-inflammatory cytokine production, and network analysis identified STAT1, EGR1, and SRC as key hub and bottleneck genes. MAB-S elicited a more robust transcriptional response at both the mRNA and miRNA levels, which was reflected in higher cytokine levels in culture supernatants. The transcriptional profiles of macrophages infected with both morphotypes were highly correlated, however, and a direct comparison identified few genes to distinguish them. Most of the induced miRNAs have previously been associated with mycobacterial infection and overall miRNA expression patterns were similarly highly correlated between the morphotypes. CONCLUSIONS: The report here details the first whole transcriptome analysis of the early macrophage response to MAB infection. The overall picture at the early stages of macrophage infection is similar to that of other mycobacteria, reflected in a core type I IFN and pro-inflammatory cytokine response. Large-scale transcriptional differences in the host response to the different MAB morphotypes are not evident in the early stages of infection, however the subset of genes with distinct expression profiles suggest potentially interesting differences in internal trafficking of MAB within macrophages. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2246-1) contains supplementary material, which is available to authorized users

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data

Pharmacogenomics Study of Thiazide Diuretics and QT Interval in Multi-Ethnic Populations: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common SNPs modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic, and cross-phenotype genome-wide analyses of European (66%), African American (15%), and Hispanic (19%) populations (N=78,199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5×10−8), we found suggestive evidence (P<5×10−6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (e.g. NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions