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1.
Eur J Cancer ; 144: 192-199, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33370644

RESUMO

BACKGROUND: The clinical differentiation of face and scalp lesions (FSLs) is challenging even for trained dermatologists. Studies comparing the diagnostic performance of a convolutional neural network (CNN) with dermatologists in FSL are lacking. METHODS: A market-approved CNN (Moleanalyzer-Pro, FotoFinder Systems) was used for binary classifications of 100 dermoscopic images of FSL. The same lesions were used in a two-level reader study including 64 dermatologists (level I: dermoscopy only; level II: dermoscopy, clinical close-up images, textual information). Primary endpoints were the CNN's sensitivity and specificity in comparison with the dermatologists' management decisions in level II. Generalizability of the CNN results was tested by using four additional external data sets. RESULTS: The CNN's sensitivity, specificity and ROC AUC were 96.2% [87.0%-98.9%], 68.8% [54.7%-80.1%] and 0.929 [0.880-0.978], respectively. In level II, the dermatologists' management decisions showed a mean sensitivity of 84.2% [82.2%-86.2%] and specificity of 69.4% [66.0%-72.8%]. When fixing the CNN's specificity at the dermatologists' mean specificity (69.4%), the CNN's sensitivity (96.2% [87.0%-98.9%]) was significantly higher than that of dermatologists (84.2% [82.2%-86.2%]; p < 0.001). Dermatologists of all training levels were outperformed by the CNN (all p < 0.001). In confirmation, the CNN's accuracy (83.0%) was significantly higher than dermatologists' accuracies in level II management decisions (all p < 0.001). The CNN's performance was largely confirmed in three additional external data sets but particularly showed a reduced specificity in one Australian data set including FSL on severely sun-damaged skin. CONCLUSIONS: When applied as an assistant system, the CNN's higher sensitivity at an equivalent specificity may result in an improved early detection of face and scalp skin cancers.

2.
Eur J Cancer ; 135: 39-46, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534243

RESUMO

BACKGROUND: Convolutional neural networks (CNNs) have shown a dermatologist-level performance in the classification of skin lesions. We aimed to deliver a head-to-head comparison of a conventional image analyser (CIA), which depends on segmentation and weighting of handcrafted features, to a CNN trained by deep learning. METHODS: Cross-sectional study using a real-world, prospectively acquired, dermoscopic dataset of 1981 skin lesions to compare the diagnostic performance of a market-approved CNN (Moleanalyzer-Pro™, developed in 2018) to a CIA (Moleanalyzer-3™/Dynamole™; developed in 2004, all FotoFinder Systems Inc, Germany). As a reference standard, we used histopathological diagnoses (n = 785) or, in non-excised benign lesions (n = 1196), expert consensus plus an uneventful follow-up by sequential digital dermoscopy for at least 2 years. RESULTS: A total of 281 malignant lesions and 1700 benign lesions from 435 patients (62.2% male, mean age: 52 years) were prospectively imaged. The CNN showed a sensitivity of 77.6% (95% confidence interval [CI]: [72.4%-82.1%]), specificity of 95.3% (95% CI: [94.2%-96.2%]), and receiver operating characteristic (ROC)-area under the curve (AUC) of 0.945 (95% CI: [0.930-0.961]). In contrast, the CIA achieved a sensitivity of 53.4% (95% CI: [47.5%-59.1%]), specificity of 86.6% (95% CI: [84.9%-88.1%]) and ROC-AUC of 0.738 (95% CI: [0.701-0.774]). The data set included melanomas originally diagnosed by dynamic changes during sequential digital dermoscopy (52 of 201, 20.6%), which reduced the sensitivities of both classifiers. Pairwise comparisons of sensitivities, specificities, and ROC-AUCs indicated a clear outperformance by the CNN (all p < 0.001). CONCLUSIONS: The superior diagnostic performance of the CNN argues against a continued application of former CIAs as an aide to physicians' clinical management decisions.

3.
Eur J Cancer ; 127: 21-29, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31972395

RESUMO

BACKGROUND: Deep learning convolutional neural networks (CNNs) show great potential for melanoma diagnosis. Melanoma thickness at diagnosis among others depends on melanoma localisation and subtype (e.g. advanced thickness in acrolentiginous or nodular melanomas). The question whether CNN may counterbalance physicians' diagnostic difficulties in these melanomas has not been addressed. We aimed to investigate the diagnostic performance of a CNN with approval for the European market across different melanoma localisations and subtypes. METHODS: The current market version of a CNN (Moleanalyzer-Pro®, FotoFinder Systems GmbH, Bad Birnbach, Germany) was used for classifications (malignant/benign) in six dermoscopic image sets. Each set included 30 melanomas and 100 benign lesions of related localisations and morphology (set-SSM: superficial spreading melanomas and macular nevi; set-LMM: lentigo maligna melanomas and facial solar lentigines/seborrhoeic keratoses/nevi; set-NM: nodular melanomas and papillomatous/dermal/blue nevi; set-Mucosa: mucosal melanomas and mucosal melanoses/macules/nevi; set-AMskin: acrolentiginous melanomas and acral (congenital) nevi; set-AMnail: subungual melanomas and subungual (congenital) nevi/lentigines/ethnical type pigmentations). RESULTS: The CNN showed a high-level performance in set-SSM, set-NM and set-LMM (sensitivities >93.3%, specificities >65%, receiver operating characteristics-area under the curve [ROC-AUC] >0.926). In set-AMskin, the sensitivity was lower (83.3%) at a high specificity (91.0%) and ROC-AUC (0.928). A limited performance was found in set-mucosa (sensitivity 93.3%, specificity 38.0%, ROC-AUC 0.754) and set-AMnail (sensitivity 53.3%, specificity 68.0%, ROC-AUC 0.621). CONCLUSIONS: The CNN may help to partly counterbalance reduced human accuracies. However, physicians need to be aware of the CNN's limited diagnostic performance in mucosal and subungual lesions. Improvements may be expected from additional training images of mucosal and subungual sites.


Assuntos
Aprendizado Profundo , Melanoma/classificação , Melanoma/diagnóstico , Redes Neurais de Computação , Idoso , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos
4.
Eur J Hum Genet ; 27(11): 1716-1723, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31227809

RESUMO

Genome-wide association studies have led in the past to the discovery of susceptibility genes for many diseases including cancer and inflammatory conditions. However, a number of these studies did not realise their full potential. A first critical step in developing such large-scale studies is the choice of genotyping array with respect to the study goal. Coverage is the central criterion for array evaluation. We distinguish between estimates of global coverage across the genome, coverage for each chromosome, coverage for selected pathways and the coverage for genes of interest. Here, we focus on inflammatory and immunological pathways and genes relevant for haematopoietic stem cell transplantation. We compared three arrays: the Infinium Global Screening Array-24 v1.0, the Infinium OncoArray-500 K BeadChip and the Infinium PsychArray-24 v1.2 BeadChip. We employed the European population from the 1000 Genomes Project as reference genome. Global coverage was found to range between 12.2 and 14.2% whereas coverage for a selected pathway ranged from 6.2 to 13.2% and gene coverage ranged from 0 to 54.1%. The Global Screening Array outperformed both other arrays in terms of global coverage, for most chromosomes, most considered pathways and most genes. When selecting suitable arrays for a new study, the coverage of pathways or genes of interest should be considered in addition to global coverage. Local coverage should be regarded when discussing association findings inconsistent across studies and can be useful in data analysis and decision making for additional genotyping.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Cromossomos , Genoma Humano , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos
5.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

6.
Cancer Epidemiol Biomarkers Prev ; 28(5): 935-942, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30700444

RESUMO

BACKGROUND: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. METHODS: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. RESULTS: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. CONCLUSIONS: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. IMPACT: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.


Assuntos
Adenocarcinoma de Pulmão/sangue , Plaquetas/patologia , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma de Células Escamosas/sangue , Neoplasias Pulmonares/sangue , Carcinoma de Pequenas Células do Pulmão/sangue , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Análise da Randomização Mendeliana , Contagem de Plaquetas , Polimorfismo de Nucleotídeo Único , Prognóstico , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
7.
Front Oncol ; 8: 396, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319965

RESUMO

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.

8.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
9.
Int Arch Occup Environ Health ; 91(8): 937-950, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29971594

RESUMO

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.


Assuntos
Carcinógenos Ambientais/toxicidade , Neoplasias Pulmonares/genética , Neoplasias Induzidas por Radiação/genética , Proteínas do Tecido Nervoso/genética , Doenças Profissionais/genética , Radônio/toxicidade , Receptores Nicotínicos/genética , Estudos de Casos e Controles , Dano ao DNA/efeitos da radiação , Feminino , Marcadores Genéticos/efeitos da radiação , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mineração , Exposição Ocupacional/efeitos adversos , Fatores de Risco , Ubiquitinação/efeitos da radiação , Urânio
10.
Int J Radiat Biol ; 94(3): 272-281, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29319401

RESUMO

PURPOSE: Age dependent radiation sensitivity for DNA damage after in vitro blood exposure by computer tomography (CT) was investigated. MATERIALS AND METHODS: Radiation biomarkers (dicentrics and gammaH2AX) in blood samples of newborns, children under five years and adults after sham exposure (0 mGy), low-dose (41 mGy) and high-dose (978 mGy) in vitro CT exposure were analyzed. RESULTS: Significantly higher levels of dicentric induction were found for the single and combined newborns/children group compared to adults, by a factor of 1.48 (95% CI 1.30-1.68), after exposure to 978 mGy. Although a significant dose response for damage induction and dose-dependent repair was found, the gammaH2AX assay did not show an age-dependent increase in DNA damage in newborns/children compared to adults. This was the case for the gammaH2AX levels after repair time intervals of 30 minutes and 24 hours, after correcting for the underlying background damage. For the low dose of 41 mGy, the power of the dicentric assay was also not sufficient to detect an age-dependent effect in the sample size investigated. CONCLUSION: A 1.5-fold increased level of dicentric aberrations is detected in newborns and children under five years after 1 Gy radiation exposure.


Assuntos
Envelhecimento/genética , Envelhecimento/efeitos da radiação , Dano ao DNA , Tomografia Computadorizada por Raios X/efeitos adversos , Adulto , Envelhecimento/metabolismo , Criança , Aberrações Cromossômicas/efeitos da radiação , Relação Dose-Resposta à Radiação , Feminino , Histonas/metabolismo , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Mol Carcinog ; 57(2): 216-224, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29071797

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , MAP Quinase Quinase Quinases , Locos de Características Quantitativas/genética , Risco
12.
Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373

RESUMO

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.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
13.
Carcinogenesis ; 38(5): 541-551, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28383684

RESUMO

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.


Assuntos
Proteínas de Transporte/genética , Grupo com Ancestrais do Continente Europeu/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Metilação de DNA , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Neoplasias Pulmonares/patologia , Razão de Chances , Polimorfismo de Nucleotídeo Único , Risco , Fatores de Risco
14.
Sci Rep ; 7(1): 825, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28400551

RESUMO

The T-cell protein tyrosine phosphatase (TCPTP) pathway consists of signaling events mediated by TCPTP. Mutations and genetic variants of some genes in the TCPTP pathway are associated with lung cancer risk and survival. In the present study, we first investigated associations of 5,162 single nucleotide polymorphisms (SNPs) in 43 genes of this TCPTP pathway with lung cancer risk by using summary data of six published genome-wide association studies (GWAS) of 12,160 cases and 16,838 controls. We identified 11 independent SNPs in eight genes after correction for multiple comparisons by a false discovery rate <0.20. Then, we performed in silico functional analyses for these 11 SNPs by eQTL analysis, two of which, PTPN2 SNPs rs2847297 and rs2847282, were chosen as tagSNPs. We further included two additional GWAS datasets of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls), and the overall effects of these two SNPs among all eight GWAS studies remained significant (OR = 0.95, 95% CI = 0.92-0.98, and P = 0.004 for rs2847297; OR = 0.95, 95% CI = 0.92-0.99, and P = 0.009 for rs2847282). In conclusion, the PTPN2 rs2847297 and rs2847282 may be potential susceptible loci for lung cancer risk.


Assuntos
Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Estudo de Associação Genômica Ampla , Humanos
15.
PLoS One ; 12(3): e0173339, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28273134

RESUMO

INTRODUCTION: Gene-set analysis (GSA) is an approach using the results of single-marker genome-wide association studies when investigating pathways as a whole with respect to the genetic basis of a disease. METHODS: We performed a meta-analysis of seven GSAs for lung cancer, applying the method META-GSA. Overall, the information taken from 11,365 cases and 22,505 controls from within the TRICL/ILCCO consortia was used to investigate a total of 234 pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: META-GSA reveals the systemic lupus erythematosus KEGG pathway hsa05322, driven by the gene region 6p21-22, as also implicated in lung cancer (p = 0.0306). This gene region is known to be associated with squamous cell lung carcinoma. The most important genes driving the significance of this pathway belong to the genomic areas HIST1-H4L, -1BN, -2BN, -H2AK, -H4K and C2/C4A/C4B. Within these areas, the markers most significantly associated with LC are rs13194781 (located within HIST12BN) and rs1270942 (located between C2 and C4A). CONCLUSIONS: We have discovered a pathway currently marked as specific to systemic lupus erythematosus as being significantly implicated in lung cancer. The gene region 6p21-22 in this pathway appears to be more extensively associated with lung cancer than previously assumed. Given wide-stretched linkage disequilibrium to the area APOM/BAG6/MSH5, there is currently simply not enough information or evidence to conclude whether the potential pleiotropy of lung cancer and systemic lupus erythematosus is spurious, biological, or mediated. Further research into this pathway and gene region will be necessary.


Assuntos
Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Transdução de Sinais , Estudos de Casos e Controles , Mapeamento Cromossômico , Biologia Computacional/métodos , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
16.
Sci Rep ; 7: 44634, 2017 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-28304396

RESUMO

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Processamento de RNA/genética , Humanos , Desequilíbrio de Ligação/genética , Anotação de Sequência Molecular , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Fatores de Risco
17.
Mol Carcinog ; 56(6): 1663-1672, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28150878

RESUMO

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.


Assuntos
Família 4 do Citocromo P450/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Família 4 do Citocromo P450/metabolismo , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Neoplasias Pulmonares/metabolismo , Transdução de Sinais
18.
Mol Carcinog ; 56(4): 1227-1238, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27805284

RESUMO

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.


Assuntos
Exorribonucleases/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Estabilidade de RNA , RNA Mensageiro/genética , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Pulmão/patologia , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Locos de Características Quantitativas , RNA Mensageiro/química
19.
Sci Rep ; 6: 34234, 2016 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-27713484

RESUMO

Lung cancer etiology is multifactorial, and growing evidence has indicated that long non-coding RNAs (lncRNAs) are important players in lung carcinogenesis. We performed a large-scale meta-analysis of 690,564 SNPs in 15,531 autosomal lncRNAs by using datasets from six previously published genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium in populations of European ancestry. Previously unreported significant SNPs (P value < 1 × 10-7) were further validated in two additional independent lung cancer GWAS datasets from Harvard University and deCODE. In the final meta-analysis of all eight GWAS datasets with 17,153 cases and 239,337 controls, a novel risk SNP rs114020893 in the lncRNA NEXN-AS1 region at 1p31.1 remained statistically significant (odds ratio = 1.17; 95% confidence interval = 1.11-1.24; P = 8.31 × 10-9). In further in silico analysis, rs114020893 was predicted to change the secondary structure of the lncRNA. Our finding indicates that SNP rs114020893 of NEXN-AS1 at 1p31.1 may contribute to lung cancer susceptibility.


Assuntos
Neoplasias Pulmonares/genética , Conformação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Fatores de Risco
20.
J Dtsch Dermatol Ges ; 14(8): 797-806, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27509414

RESUMO

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.


Assuntos
Microscopia Confocal , Dermatopatias/diagnóstico , Humanos , Dermatopatias/terapia
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