Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).

Confirmation of Dissipative Sensing Enhancement in a Microresonator Using Multimode Input.

Optical microresonators have proven to be especially useful for sensing applications. In most cases, the sensing mechanism is dispersive, where the resonance frequency of a mode shifts in response to a change in the ambient index of refraction. It is also possible to conduct dissipative sensing, in which absorption by an analyte causes measurable changes in the mode linewidth and in the throughput dip depth. If the mode is overcoupled, the dip depth response can be more sensitive than the linewidth response, but overcoupling is not always easy to achieve. We have recently shown theoretically that using multimode input to the microresonator can enhance the dip-depth sensitivity by a factor of several thousand relative to that of single-mode input and by a factor of nearly 100 compared to the linewidth sensitivity. Here, we experimentally confirm these enhancements using an absorbing dye dissolved in methanol inside a hollow bottle resonator. We review the theory, describe the setup and procedure, detail the fabrication and characterization of an asymmetrically tapered fiber to produce multimode input, and present sensing enhancement results that agree with all the predictions of the theory.

Iam hiQ-a novel pair of accuracy indices for imputed genotypes.

BACKGROUND: Imputation of untyped markers is a standard tool in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy with which genotypes are imputed is fundamental. Several accuracy measures have been proposed and some are implemented in imputation software, unfortunately diversely across platforms. In the present paper, we introduce Iam hiQ, an independent pair of accuracy measures that can be applied to dosage files, the output of all imputation software. Iam (imputation accuracy measure) quantifies the average amount of individual-specific versus population-specific genotype information in a linear manner. hiQ (heterogeneity in quantities of dosages) addresses the inter-individual heterogeneity between dosages of a marker across the sample at hand. RESULTS: Applying both measures to a large case-control sample of the International Lung Cancer Consortium (ILCCO), comprising 27,065 individuals, we found meaningful thresholds for Iam and hiQ suitable to classify markers of poor accuracy. We demonstrate how Manhattan-like plots and moving averages of Iam and hiQ can be useful to identify regions enriched with less accurate imputed markers, whereas these regions would by missed when applying the accuracy measure info (implemented in IMPUTE2). CONCLUSION: We recommend using Iam hiQ additional to other accuracy scores for variant filtering before stepping into the analysis of imputed GWAS data.

ImputAccur: fast and user-friendly calculation of genotype-imputation accuracy-measures.

BACKGROUND: ImputAccur is a software tool to measure genotype-imputation accuracy. Imputation of untyped markers is a standard approach in genome-wide association studies to close the gap between directly genotyped and other known DNA variants. However, high accuracy for imputed genotypes is fundamental. Several accuracy measures have been proposed, but unfortunately, they are implemented on different platforms, which is impractical. RESULTS: With ImputAccur, the accuracy measures info, Iam-hiQ and r2-based indices can be derived from standard output files of imputation software. Sample/probe and marker filtering is possible. This allows e.g. accurate marker filtering ahead of data analysis. CONCLUSIONS: The source code (Python version 3.9.4), a standalone executive file, and example data for ImputAccur are freely available at https://gitlab.gwdg.de/kolja.thormann1/imputationquality.git .

Preadult polytoxicomania-strong environmental underpinnings and first genetic hints.

Considering the immense societal and personal costs and suffering associated with multiple drug use or "polytoxicomania", better understanding of environmental and genetic causes is crucial. While previous studies focused on single risk factors and selected drugs, effects of early-accumulated environmental risks on polytoxicomania were never addressed. Similarly, evidence of genetic susceptibility to particular drugs is abundant, while genetic predisposition to polytoxicomania is unexplored. We exploited the GRAS data collection, comprising information on N~2000 deep-phenotyped schizophrenia patients, to investigate effects of early-life environmental risk accumulation on polytoxicomania and additionally provide first genetic insight. Preadult accumulation of environmental risks (physical or sexual abuse, urbanicity, migration, cannabis, alcohol) was strongly associated with lifetime polytoxicomania (p = 1.5 × 10-45; OR = 31.4), preadult polytoxicomania with OR = 226.6 (p = 1.0 × 10-33) and adult polytoxicomania with OR = 17.5 (p = 3.4 × 10-24). Parallel accessibility of genetic data from GRAS patients and N~2100 controls for genome-wide association (GWAS) and phenotype-based genetic association studies (PGAS) permitted the creation of a novel multiple GWAS-PGAS approach. This approach yielded 41 intuitively interesting SNPs, potentially conferring liability to preadult polytoxicomania, which await replication upon availability of suitable deep-phenotyped cohorts anywhere world-wide. Concisely, juvenile environmental risk accumulation, including cannabis and alcohol as starter/gateway drugs, strongly predicts polytoxicomania during adolescence and adulthood. This pivotal message should launch more effective sociopolitical measures to prevent this deleterious psychiatric condition.

Nailfold videocapillaroscopy identifies microvascular pathologies in psoriasis vulgaris: Results of a prospective controlled study.

BACKGROUND: Psoriasis is considered an independent cardiovascular risk factor, evidentially driving atherosclerosis. However, little is known about changes in the microvasculature of non-lesional skin in psoriasis patients. This study systematically examined capillary pathologies in psoriasis patients by digital video nailfold capillaroscopy. PATIENTS AND METHODS: Prospective study comparing nailfold capillaries of psoriasis patients with those of healthy controls. Nailfold capillaries were evaluated for 21 parameters and results were correlated with characteristics of patients and psoriatic disease, laboratory parameters, and measurements of carotid intima-media thickness. RESULTS: 77 psoriasis patients (24 patients with additional psoriatic arthritis) and 71 controls were well-matched for demographic features and for relevant confounding factors causing microangiopathy. In comparison with controls, psoriasis patients showed a significant loss of capillaries, capillary expansion with increased ramifications and tortuosity and capillary irregularities. Moreover, in psoriasis patients we found significantly elevated serum markers of inflammation and significantly increased intima-media-thickness measurements. We found no effect of disease duration nor disease activity on capillary changes. CONCLUSIONS: Nailfold capillaries of psoriasis patients showed marked microvascular abnormalities accompanied by increased markers of systemic inflammation and atherosclerosis. Prospective cohort studies are needed to assess the role of nailfold capillaroscopy for predicting the cardiovascular risk of psoriasis patients.

Mikrovaskuläre Pathologien bei Patienten mit Psoriasis vulgaris mittels Nagelfalzkapillarmikroskopie identifiziert: Ergebnisse einer prospektiven kontrollierten Studie.

Hintergrund: Die Psoriasis gilt als unabhängiger kardiovaskulärer Risikofaktor und Treiber einer Atherogenese. Mikrovaskuläre Veränderungen in psoriatischen Plaques sind gut beschrieben, wohingegen Veränderungen außerhalb betroffener Hautareale kaum untersucht wurden. In dieser Studie wurden Nagelfalzkapillaren von Psoriasispatienten in nicht betroffener Haut systematisch untersucht. Patienten und Methodik: Prospektive Studie mit Untersuchung von Nagelfalzkapillaren bei Psoriasispatienten im Vergleich zu gesunden Kontrollen mittels digitaler Videokapillarmikroskopie. Es wurden 21 kapillarmikroskopische Parameter bewertet und die Ergebnisse mit Charakteristika der Patienten und der Psoriasiserkrankung, mit Laborparametern und Messungen der Intima-Media-Dicke der Arteria carotis communis korreliert. Ergebnisse: Die 77 Psoriasispatienten (24 mit zusätzlicher Psoriasisarthritis) und 71 Kontrollen zeigten sich hinsichtlich demographischer Merkmale und relevanter Einflussfaktoren für eine Mikroangiopathie ausbalanciert. Im Vergleich zur Kontrollgruppe zeigten Psoriasispatienten eine signifikante Minderung der kapillaren Dichte, häufigere Kapillarerweiterung mit mehr Verzweigungen, Torquierungen und kapillaren Unregelmäßigkeiten. Zusätzlich zeigten Psoriasispatienten signifikant höhere inflammatorische Serummarker und eine gesteigerte Intima-Media-Dicke. In unserem Kollektiv bestand kein Zusammenhang zwischen Krankheitsdauer oder Schweregrad der Psoriasis und spezifischen Kapillarveränderungen. Schlussfolgerungen: Die Nagelfalzkapillaren der untersuchten Psoriasispatienten zeigten ausgeprägte mikrovaskuläre Veränderungen, welche mit erhöhten Markern einer systemischen Entzündung und Frühzeichen einer Atherosklerose korrelierten. Weitere Studien sind erforderlich, um die Rolle der digitalen Videokapillarmikroskopie in der Bewertung des kardiovaskulären Risikos von Psoriasispatienten zu untersuchen.

Auswirkungen des "dunklen Rand-Artefakts" in dermatoskopischen Bildern auf die diagnostische Leistungsfähigkeit eines deep learning neuronalen Netzwerkes mit Marktzulassung.

HINTERGRUND UND ZIELE: Systeme künstlicher Intelligenz (durch "deep learning" faltende neuronale Netzwerke; engl. convolutional neural networks, CNN) erreichen inzwischen bei der Klassifikation von Hautläsionen vergleichbar gute Ergebnisse wie Dermatologen. Allerdings müssen die Limitationen solcher Systeme vor flächendeckendem klinischem Einsatz bekannt sein. Daher haben wir den Einfluss des "dunklen Rand-Artefakts" (engl. dark corner artefact; DCA) in dermatoskopischen Bildern auf die diagnostische Leistung eines CNN mit Marktzulassung zur Klassifikation von Hautläsionen untersucht. PATIENTEN UND METHODEN: Ein Datensatz aus 233 Bildern von Hautläsionen (60 maligne und 173 benigne) ohne DCA (Kontrolle) wurde digital so modifiziert, dass kleine, mittlere oder große DCA zu sehen waren. Alle 932 Bilder wurden dann mittels CNN mit Marktzulassung (Moleanalyzer-Pro® , FotoFinder Systems) auf Malignitätsscores hin analysiert. Das Spektrum reichte von 0-1; ein Score von > 0,5 wurde als maligne klassifiziert. ERGEBNISSE: In der Kontrollserie ohne DCA erreichte das CNN eine Sensitivität von 90,0 % (79,9 %-95,3 %), eine Spezifität von 96,5 % (92,6 %-98,4 %) sowie eine Fläche unter der Kurve (AUC, area under the curve) der "receiver operating characteristic" (ROC) von 0,961 (0,932-0,989). In den Datensätzen mit kleinen beziehungsweise mittleren DCA war die diagnostische Leistung vergleichbar. In den Bildersätzen mit großen DCA wurden allerdings signifikant höhere Malignitätsscores erzielt. Dies führte zu einer signifikant verminderten Spezifität (87,9 % [82,2 %-91,9 %], P < 0,001) sowie einer nicht signifikant erhöhten Sensitivität (96,7 % [88,6 %-99,1 %]). Die ROC-AUC blieb mit 0,962 (0,935-0,989) unverändert. SCHLUSSFOLGERUNGEN: Die Klassifizierung mittels des CNN war bei dermatoskopischen Bildern mit kleinen oder mittleren DCA nicht beeinträchtigt, das System zeigte jedoch Schwächen bei großen DCA. Wenn Ärzte solche Bilder zur Klassifikation mittels CNN einreichen, sollten sie sich dieser Grenzen der Technologie bewusst sein.

Dark corner artefact and diagnostic performance of a market-approved neural network for skin cancer classification.

BACKGROUND AND OBJECTIVES: Convolutional neural networks (CNN) have proven dermatologist-level performance in skin lesion classification. Prior to a broader clinical application, an assessment of limitations is crucial. Therefore, the influence of a dark tubular periphery in dermatoscopic images (also called dark corner artefact [DCA]) on the diagnostic performance of a market-approved CNN for skin lesion classification was investigated. PATIENTS AND METHODS: A prospective image set of 233 skin lesions (60 malignant, 173 benign) without DCA (control-set) was modified to show small, medium or large DCA. All 932 images were analyzed by a market-approved CNN (Moleanalyzer-Pro® , FotoFinder Systems), providing malignancy scores (range 0-1) with the cut-off > 0.5 indicating malignancy. RESULTS: In the control-set the CNN achieved a sensitivity of 90.0 % (79.9 % - 95.3 %), a specificity of 96.5 % (92.6 % - 98.4 %), and an area under the curve (AUC) of receiver operating characteristics (ROC) of 0.961 (0.932 - 0.989). Comparable diagnostic performance was observed in the DCAsmall-set and DCAmedium-set. Conversely, in the DCAlarge-set significantly increased malignancy scores triggered a significantly decreased specificity (87.9 % [82.2 % - 91.9 %], P < 0.001), non-significantly increased sensitivity (96.7 % [88.6 % - 99.1 %]) and unchanged ROC-AUC of 0.962 (0.935 - 0.989). CONCLUSIONS: Convolutional neural network classification was robust in images with small and medium DCA, but impaired in images with large DCA. Physicians should be aware of this limitation when submitting images to CNN classification.

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

Novel genetic variants in the P38MAPK pathway gene ZAK and susceptibility to lung cancer.

The P38MAPK pathway participates in regulating cell cycle, inflammation, development, cell death, cell differentiation, and tumorigenesis. Genetic variants of some genes in the P38MAPK pathway are reportedly associated with lung cancer risk. To substantiate this finding, we used six genome-wide association studies (GWASs) to comprehensively investigate the associations of 14 904 single nucleotide polymorphisms (SNPs) in 108 genes of this pathway with lung cancer risk. We identified six significant lung cancer risk-associated SNPs in two genes (CSNK2B and ZAK) after correction for multiple comparisons by a false discovery rate (FDR) <0.20. After removal of three CSNK2B SNPs that are located in the same locus previously reported by GWAS, we performed the LD analysis and found that rs3769201 and rs7604288 were in high LD. We then chose two independent representative SNPs of rs3769201 and rs722864 in ZAK for further analysis. We also expanded the analysis by including these two SNPs from additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26 380 controls). The overall effects of these two SNPs were assessed using all eight GWAS datasets (OR = 0.92, 95%CI = 0.89-0.95, and P = 1.03 × 10-5 for rs3769201; OR = 0.91, 95%CI = 0.88-0.95, and P = 2.03 × 10-6 for rs722864). Finally, we performed an expression quantitative trait loci (eQTL) analysis and found that these two SNPs were significantly associated with ZAK mRNA expression levels in lymphoblastoid cell lines. In conclusion, the ZAK rs3769201 and rs722864 may be functional susceptibility loci for lung cancer risk.

Genetic modifiers of radon-induced lung cancer risk: a genome-wide interaction study in former uranium miners.

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.

Functional variants in DCAF4 associated with lung cancer risk in European populations.

Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16 599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12 160 cases and 16 838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0.91, 1.09 and 1.09, respectively; 95% confidence interval = 0.88-0.95, 1.05-1.14 and 1.05-1.13, respectively; and P = 3.99 × 10-6, 4.97 × 10-5 and 1.44 × 10-5, respectively) after multiple comparison correction by a false discovery rate <0.05. Since SNP rs12587742 is located within the promoter region and one CpG island of DCAF4, we further performed in silico functional analyses and found that the rs12587742 variant A allele was associated with an increased mRNA expression (P = 2.20 × 10-16, 1.79 × 10-13 and 0.001 in blood cells, normal lung tissues and tumor tissues of lung squamous carcinoma, respectively) and a decreased methylation status (P = 2.48 × 10-9 and 0.032 in adipose and lung tumor tissues, respectively). Moreover, evidence from differential expression analyses further supported an oncogenic effect of DCAF4 on lung cancer, with higher mRNA levels in both lung squamous carcinoma and adenocarcinoma (P = 4.48 × 10-11 and 1.22 × 10-9, respectively) than in adjacent normal tissues. Taken together, our results suggest that rs12587742 is associated with an increased lung cancer risk, possibly by up-regulating mRNA expression and decreasing methylation status of DCAF4.

Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions.

Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general.

Pathway-analysis of published genome-wide association studies of lung cancer: A potential role for the CYP4F3 locus.

The fatty acids (FAs) metabolism is suggested to play a pivotal role in the development of lung cancer, and we explored that by conducting a pathway-based analysis. We performed a meta-analysis of published datasets of six genome wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium, which included 12 160 cases with lung cancer and 16 838 cancer-free controls. A total of 30 722 single-nucleotide polymorphisms (SNPs) from 317 genes relevant to FA metabolic pathways were identified. An additional dataset from the Harvard Lung Cancer Study with 984 cases and 970 healthy controls was also added to the final meta-analysis. In the initial meta-analysis, 26 of 28 SNPs that passed false discovery rate multiple tests were mapped to the CYP4F3 gene. Among the 26 top ranked hits was a proxy SNP, CYP4F3 rs4646904 (P = 8.65 × 10-6 , FDR = 0.018), which is suggested to change splicing pattern/efficiency and to be associated with gene expression levels. However, after adding data of rs4646904 from the Harvard GWAS, the significance in the combined analysis was reduced to P = 3.52 × 10-3 [odds ratio (OR) = 1.07, 95% confidence interval (95%CI) = 1.03-1.12]. Interestingly, the small Harvard dataset also pointed to the same direction of the association in subgroups of smokers (OR = 1.07) and contributed to a combined OR of 1.13 (95% CI = 1.06-1.20, P = 6.70 × 10-5 ). The results suggest that a potentially functional SNP in CYP4F3 (rs4646904) may contribute to the etiology of lung cancer, especially in smokers. Additional mechanistic studies are warranted to unravel the potential biological significance of the finding.

Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

PURPOSE: mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. EXPERIMENTAL DESIGN: Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. RESULTS: This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of <0.05. Among the 11 newly identified SNPs in CNOT6, which were in high linkage disequilibrium, the rs2453176 with a RegulomDB score "1f" was chosen as the tagSNP for further analysis. We found that the rs2453176 T allele was significantly associated with lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. CONCLUSION: The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc.

Polymorphisms of the centrosomal gene (FGFR1OP) and lung cancer risk: a meta-analysis of 14,463 cases and 44,188 controls.

Centrosome abnormalities are often observed in premalignant lesions and in situ tumors and have been associated with aneuploidy and tumor development. We investigated the associations of 9354 single-nucleotide polymorphisms (SNPs) in 106 centrosomal genes with lung cancer risk by first using the summary data from six published genome-wide association studies (GWASs) of the Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16 838 controls) and then conducted in silico replication in two additional independent lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1319 cases and 26,380 controls). A total of 44 significant SNPs with false discovery rate (FDR) ≤ 0.05 were mapped to one novel gene FGFR1OP and two previously reported genes (TUBB and BRCA2). After combined the results from TRICL with those from Harvard and deCODE, the most significant association (P combined = 8.032 × 10(-6)) was with rs151606 within FGFR1OP. The rs151606 T>G was associated with an increased risk of lung cancer [odds ratio (OR) = 1.10, 95% confidence interval (95% CI) = 1.05-1.14]. Another significant tagSNP rs12212247 T>C (P combined = 9.589 × 10(-6)) was associated with a decreased risk of lung cancer (OR = 0.93, 95% CI = 0.90-0.96). Further in silico functional analyzes revealed that rs151606 might affect transcriptional regulation and result in decreased FGFR1OP expression (P trend = 0.022). The findings shed some new light on the role of centrosome abnormalities in the susceptibility to lung carcinogenesis.

Informed genome-wide association analysis with family history as a secondary phenotype identifies novel loci of lung cancer.

Lung cancer is the leading cause of cancer death worldwide. Although several genetic variants associated with lung cancer have been identified in the past, stringent selection criteria of genome-wide association studies (GWAS) can lead to missed variants. The objective of this study was to uncover missed variants by using the known association between lung cancer and first-degree family history of lung cancer to enrich the variant prioritization for lung cancer susceptibility regions. In this two-stage GWAS study, we first selected a list of variants associated with both lung cancer and family history of lung cancer in four GWAS (3,953 cases, 4,730 controls), then replicated our findings for 30 variants in a meta-analysis of four additional studies (7,510 cases, 7,476 controls). The top ranked genetic variant rs12415204 in chr10q23.33 encoding FFAR4 in the Discovery set was validated in the Replication set with an overall OR of 1.09 (95% CI=1.04, 1.14, P=1.63×10(-4)). When combining the two stages of the study, the strongest association was found in rs1158970 at Ch4p15.2 encoding KCNIP4 with an OR of 0.89 (95% CI=0.85, 0.94, P=9.64×10(-6)). We performed a stratified analysis of rs12415204 and rs1158970 across all eight studies by age, gender, smoking status, and histology, and found consistent results across strata. Four of the 30 replicated variants act as expression quantitative trait loci (eQTL) sites in 1,111 nontumor lung tissues and meet the genome-wide 10% FDR threshold.

Morphologische Kriterien vesikulobullöser Hauterkrankungen in der konfokalen In-vivo-Laserscanmikroskopie.

HINTERGRUND UND ZIELVORGABEN: Konfokale Laserscanmikroskopie (Reflectance confocal microscopy; RCM) kann eine nützliche Methode für die genaue, schnelle und nicht-invasive Diagnose für vesikullobullöse Hauterkrankungen (VSD) am Krankenbett sein. Das primäre Ergebnis dieser Studie war eine deskriptive statistische Analyse von RCM-Merkmalen, die mit einer ausgewählten Gruppe an VSD einhergehen. PATIENTEN UND METHODEN: Monozentrische Beobachtungsstudie an einer Universitätsklinik für Dermatologie. Vierzig Hautläsionen bei 24 Patienten mit bullösem Pemphigoid (BP), Infektion mit Varizella Zoster (VZI) oder allergischer Kontaktdermatitis (ACD) wurden ausgewertet. ERGEBNISSE: Patienten mit BP, VZI und ACD wurden auf die Anwesenheit eines großen Spektrums an RCM-Merkmalen hin untersucht, darunter die histopathologische Korrelation von Spongiose, Vesikel/Hautblasen, epidermaler Nekrose, pleomorphen, ballonierte Keratinozyten und entzündlichen Infiltraten. Die drei Erkrankungen zeigten spezifische Muster für Auftreten dieser RCM-Merkmale. Wir identifizierten mit Hilfe einer multivariaten Regressionsanalyse einen Satz morphologischer Merkmale bei BP (Vesikel/Hautblasen an der dermoepidermalen Junktionszone, entzündliche Infiltrate in Hautblasen und basalen Epidermisschichten, Spongiose in basalen Epidermisschichten), VZI (Akantholyse im Stratum spinosum, epidermale Nekrose, pleomorphe, ballonierte Keratinozyten, multinukleäre Riesenzellen) und ACD (Mikrovesikel, Spongiose und auffällige entzündliche Infiltrate im Stratum granulosum/spinosum). SCHLUSSFOLGERUNGEN: RCM scheint ein nützliches Werkzeug bei der Analyse und der Unterscheidung einer ausgewählten Gruppe von VSDs zu sein und bietet eine gute Korrelation mit histopathologischen Untersuchungsergebnissen.

Morphologic criteria of vesiculobullous skin disorders by in vivo reflectance confocal microscopy.

BACKGROUND AND OBJECTIVES: Reflectance confocal microscopy (RCM) may be a useful method for accurate, rapid, and noninvasive bedside diagnosis of vesiculobullous skin diseases (VSD). The main outcome measure of this study was a descriptive statistical analysis of RCM features associated with selected group of VSD. PATIENTS AND METHODS: Single-center, observational study at a university-based dermatology department. Forty skin lesions in 24 patients with bullous pemphigoid (BP), varicella zoster virus infection (VZI), or allergic contact dermatitis (ACD) were assessed. RESULTS: Patients with BP, VZI, and ACD were assessed for the presence of a large spectrum of RCM features, among others including histopathological correlates for spongiosis, vesicles/blisters, epidermal necrosis, pleomorphic ballooned keratinocytes, and inflammatory infiltrate. The three conditions showed distinct patterns of occurrence with respect to these RCM features. Using a multivariate regression model, we identified sets of morphologic features in BP (vesicles/blisters at the dermoepidermal junction, inflammatory infiltrate within blisters and basal epidermal layers, spongiosis in basal epidermal layers), VZI (acantholysis in the stratum spinosum, epidermal necrosis, pleomorphic ballooned keratinocytes, multinucleated giant cells), and ACD (microvesicles, spongiosis, and prominent inflammatory infiltrate in the stratum granulosum/spinosum). CONCLUSIONS: RCM seems to be a useful tool in the evaluation and differentiation of a selected group of VSD, and offers a good correlation with histopathological findings.