Impact on Disease Development, Genomic Location and Biological Function of Copy Number Alterations in Non-Small Cell Lung Cancer

Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., non-involved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, non-involved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells

Somatic mutations affect key pathways in lung adenocarcinoma

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well- classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers - including NF1, APC, RB1 and ATM - and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.National Human Genome Research InstituteWe thank A. Lash, M.F. Zakowski, M.G. Kris and V. Rusch for intellectual contributions, and many members of the Baylor Human Genome Sequencing Center, the Broad Institute of Harvard and MIT, and the Genome Center at Washington University for support. This work was funded by grants from the National Human Genome Research Institute to E.S.L., R.A.G. and R.K.W.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62885/1/nature07423.pd

European Radiology / Inter- and intra-reader agreement for gadoxetic acidenhanced MRI parameter readings in patients with chronic liver diseases

Objectives To examine inter- and intra-observer agreement for four simple hepatobiliary phase (HBP)based scores on gadoxetic acid (GA)enhanced MRI and their correlation with liver function in patients with mixed chronic liver disease (CLD). Methods This single-center, retrospective study included 287 patients (62% male, 38% female, mean age 53.5 13.7 years) with mixed CLD (20.9% hepatitis C, 19.2% alcoholic liver disease, 8% hepatitis B) who underwent GA-enhanced MRI of the liver for clinical care between 2010 and 2015. Relative liver enhancement (RLE), contrast uptake index (CUI), hepatic uptake index (HUI), and liver-to-spleen contrast index (LSI) were calculated by two radiologists independently using unenhanced and GA-enhanced HPB (obtained 20 min after GA administration) images; 50 patients selected at random were reviewed twice by one reader to assess intra-observer reliability. Agreement was assessed by intraclass correlation coefficient (ICC). The albumin-bilirubin (ALBI) score, the model of end-stage liver disease (MELD), and the Child-Turcotte-Pugh (CTP) score were calculated as standards of reference for hepatic function. Results Intra-observer ICCs ranged from 0.814 (0.6680.896) for CUI to 0.969 (0.9450.983) for RLE. Inter-observer ICCs ranged from 0.777 (0.6050.874) for HUI to 0.979 (0.9630.988) for RLE. All HBP-based scores correlated significantly (all p < 0.001) with the ALBI, MELD, and CTP scores and were able to discriminate patients with a MELD score 15 versus 14, with area under the curve values ranging from 0.760 for RLE to 0.782 for HUI. Conclusion GA-enhanced, MRI-derived, HBP-based parameters showed excellent inter- and intra-observer agreement. All HBP-based parameters correlated with clinical and laboratory scores of hepatic dysfunction, with no significant differences between each other. Key Points Radiological parameters that quantify the hepatic uptake of gadoxetic acid are highly reproducible. These parameters can be used interchangeably because they correlate with each other and with scores of hepatic dysfunction. Assessment of these parameters may be helpful in monitoring disease progression.(VLID)504051

Health worker perspectives on barriers to delivery of routine tuberculosis diagnostic evaluation services in Uganda: a qualitative study to guide clinic-based interventions

BACKGROUND: Studies of the quality of tuberculosis (TB) diagnostic evaluation of patients in high burden countries have generally shown poor adherence to international or national guidelines. Health worker perspectives on barriers to improving TB diagnostic evaluation are critical for developing clinic-level interventions to improve guideline implementation. METHODS: We conducted structured, in-depth interviews with staff at six district-level health centers in Uganda to elicit their perceptions regarding barriers to TB evaluation. Interviews were transcribed, coded with a standardized framework, and analyzed to identify emergent themes. We used thematic analysis to develop a logic model depicting health system and contextual barriers to recommended TB evaluation practices. To identify possible clinic-level interventions to improve TB evaluation, we categorized findings into predisposing, enabling, and reinforcing factors as described by the PRECEDE model, focusing on potentially modifiable behaviors at the clinic-level. RESULTS: We interviewed 22 health center staff between February 2010 and November 2011. Participants identified key health system barriers hindering TB evaluation, including: stock-outs of drugs/supplies, inadequate space and infrastructure, lack of training, high workload, low staff motivation, and poor coordination of health center services. Contextual barrier challenges to TB evaluation were also reported, including the time and costs borne by patients to seek and complete TB evaluation, poor health literacy, and stigma against patients with TB. These contextual barriers interacted with health system barriers to contribute to sub-standard TB evaluation. Examples of intervention strategies that could address these barriers and are related to PRECEDE model components include: assigned mentors/peer coaching for new staff (targets predisposing factor of low motivation and need for support to conduct job duties); facilitated workshops to implement same day microscopy (targets enabling factor of patient barriers to completing TB evaluation), and recognition/incentives for good TB screening practices (targets low motivation and self-efficacy). CONCLUSIONS: Our findings suggest that health system and contextual barriers work together to impede TB diagnosis at health centers and, if not addressed, could hinder TB case detection efforts. Qualitative research that improves understanding of the barriers facing TB providers is critical to developing targeted interventions to improve TB care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12913-014-0668-0) contains supplementary material, which is available to authorized users