Methylation of the candidate biomarker TCF21 is very frequent across a spectrum of early-stage nonsmall cell lung cancers

The transcription factor TCF21 is involved in mesenchymal-to-epithelial differentiation and was shown to be aberrantly hypermethylated in lung and head and neck cancers. Because of its reported high frequency of hypermethylation in lung cancer, we sought to characterize the stages and types of non-small cell lung cancer (NSCLC) that are hypermethylated and to define the frequency of hypermethylation and associated “second hits”

Breeding value prediction for production traits in layer chickens using pedigree or genomic relationships in a reduced animal model

<p>Abstract</p> <p>Background</p> <p>Genomic selection involves breeding value estimation of selection candidates based on high-density SNP genotypes. To quantify the potential benefit of genomic selection, accuracies of estimated breeding values (EBV) obtained with different methods using pedigree or high-density SNP genotypes were evaluated and compared in a commercial layer chicken breeding line.</p> <p>Methods</p> <p>The following traits were analyzed: egg production, egg weight, egg color, shell strength, age at sexual maturity, body weight, albumen height, and yolk weight. Predictions appropriate for early or late selection were compared. A total of 2,708 birds were genotyped for 23,356 segregating SNP, including 1,563 females with records. Phenotypes on relatives without genotypes were incorporated in the analysis (in total 13,049 production records).</p> <p>The data were analyzed with a Reduced Animal Model using a relationship matrix based on pedigree data or on marker genotypes and with a Bayesian method using model averaging. Using a validation set that consisted of individuals from the generation following training, these methods were compared by correlating EBV with phenotypes corrected for fixed effects, selecting the top 30 individuals based on EBV and evaluating their mean phenotype, and by regressing phenotypes on EBV.</p> <p>Results</p> <p>Using high-density SNP genotypes increased accuracies of EBV up to two-fold for selection at an early age and by up to 88% for selection at a later age. Accuracy increases at an early age can be mostly attributed to improved estimates of parental EBV for shell quality and egg production, while for other egg quality traits it is mostly due to improved estimates of Mendelian sampling effects. A relatively small number of markers was sufficient to explain most of the genetic variation for egg weight and body weight.</p

Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SqCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SqCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, which are each observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. Additionally, we report a patient with an FGFR2-mutated oral squamous cell carcinoma who responded to the multi-targeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SqCC

Summary from an international cancer seminar focused on human papillomavirus (HPV)-positive oropharynx cancer, convened by scientists at IARC and NCI

Cancer of the oropharynx has attracted considerable attention in recent years given: (1) an increasing incidence in selected populations over the past three decades; (2) the discovery of human papillomavirus (HPV) infection as the driver of the increase, as opposed to the traditional risk factors such as tobacco (smoking and chewing) and alcohol; and (3) the promise of new prevention and treatment strategies. As a result of such developments, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI), convened the fourth Cancer Seminar meeting in November 2018 to focus on this topic. This report summarizes the proceedings: a review of recent science on the descriptive epidemiology, etiology, biology, genetics, early detection, pathology and treatment of HPV-positive oropharyngeal cancer, and the formulation of key research questions to be addressed

Diagnostic Accuracy of HPV16 Early Antigen Serology For HPV-Driven Oropharyngeal Cancer is Independent of Age and Sex

Funding information: This project was funded in part by NIH/NIDCR R01 DE025712 (Paul Brennan, Brenda Diergaarde and Neil Hayes). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework program (QLK1-2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). We thank Dr. Wolfgang Ahrens, PhD (Universität Bremen, Germany) for his support in ARCAGE study. The Carolina Head and Neck Cancer Epidemiology (CHANCE) study was supported in part by the National Cancer Institute (R01-CA90731). The Head and Neck 5000 study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707-10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Core funding was also provided through awards from Above and Beyond, University Hospitals Bristol and Weston Research Capability Funding and the NIHR Senior Investigator award to Professor Andy Ness. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The University of Pittsburgh head and neck cancer case-control study is supported by US National Institutes of Health grants P50CA097190 and P30CA047904. The MSH-PMH study was supported by Canadian Cancer Society Research Institute and Lusi Wong Programs at the Princess Margaret Hospital Foundation.Peer reviewedPublisher PD

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Integrative genomic and proteomic analyses identify targets for Lkb1 deficient metastatic lung tumors

SummaryIn mice, Lkb1 deletion and activation of KrasG12D results in lung tumors with a high penetrance of lymph node and distant metastases. We analyzed these primary and metastatic de novo lung cancers with integrated genomic and proteomic profiles and have identified gene and phosphoprotein signatures associated with Lkb1 loss and progression to invasive and metastatic lung tumors. These studies revealed that SRC is activated in Lkb1 deficient primary and metastatic lung tumors and that the combined inhibition of SRC, PI3K and MEK1/2 resulted in synergistic tumor regression. These studies demonstrate that integrated genomic and proteomic analyses can be used to identify signaling pathways that may be targeted for treatment

Estimating Dengue Transmission Intensity from Sero-Prevalence Surveys in Multiple Countries

BACKGROUND:Estimates of dengue transmission intensity remain ambiguous. Since the majority of infections are asymptomatic, surveillance systems substantially underestimate true rates of infection. With advances in the development of novel control measures, obtaining robust estimates of average dengue transmission intensity is key for assessing both the burden of disease from dengue and the likely impact of interventions. METHODOLOGY/PRINCIPAL FINDINGS:The force of infection (λ) and corresponding basic reproduction numbers (R0) for dengue were estimated from non-serotype (IgG) and serotype-specific (PRNT) age-stratified seroprevalence surveys identified from the literature. The majority of R0 estimates ranged from 1-4. Assuming that two heterologous infections result in complete immunity produced up to two-fold higher estimates of R0 than when tertiary and quaternary infections were included. λ estimated from IgG data were comparable to the sum of serotype-specific forces of infection derived from PRNT data, particularly when inter-serotype interactions were allowed for. CONCLUSIONS/SIGNIFICANCE:Our analysis highlights the highly heterogeneous nature of dengue transmission. How underlying assumptions about serotype interactions and immunity affect the relationship between the force of infection and R0 will have implications for control planning. While PRNT data provides the maximum information, our study shows that even the much cheaper ELISA-based assays would provide comparable baseline estimates of overall transmission intensity which will be an important consideration in resource-constrained settings

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts