RESUMEN
Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.
RESUMEN
Single nucleotide substitutions are the most common type of somatic mutations in cancer genome. The goal of this study was to use publicly available somatic mutation data to quantify negative and positive selection in individual lung tumors and test how strength of directional and absolute selection is associated with clinical features. The analysis found a significant variation in strength of selection (both negative and positive) among tumors, with median selection tending to be negative even though tumors with strong positive selection also exist. Strength of selection estimated as the density of missense mutations relative to the density of silent mutations showed only a weak correlation with tumor mutation burden. In the "all histology together" analysis we found that absolute strength of selection was strongly correlated with all clinically relevant features analyzed. In histology-stratified analysis selection was strongest in small cell lung cancer. Selection in adenocarcinoma was somewhat higher compared to squamous cell carcinoma. The study suggests that somatic mutation- based quantifying of directional and absolute selection in individual tumors can be a useful biomarker of tumor aggressiveness.
Asunto(s)
Neoplasias Pulmonares , Mutación , Selección Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Biomarcadores de Tumor/genética , Mutación Missense , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologíaRESUMEN
BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Adulto , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Metilación de ADN , Neoplasias Pulmonares/genética , Estudio de Asociación del Genoma Completo , Epigénesis Genética , Biomarcadores , Islas de CpGRESUMEN
BACKGROUND: Many patients with glioblastoma multiforme (GBM) develop deep venous thrombosis or pulmonary emboli. Cell-free circulating mitochondria increase after brain injury and are associated with coagulopathy. OBJECTIVES: This study evaluated whether mitochondria play a role in the GBM-induced hypercoagulable state. METHODS: We examined the correlation between cell-free circulating mitochondria and venous thrombosis in patients with GBM and the impact of mitochondria on venous thrombosis in mice with inferior vena cava stenosis. RESULTS: Using plasma samples of 82 patients with GBM, we found that patients with GBM had a higher number of mitochondria in their plasma (GBM with venous thromboembolism [VTE],: 2.8 × 107 mitochondria/mL; GBM without VTE, 1.9 × 107 mitochondria/mL) than that in healthy control subjects (n = 17) (0.3 × 107 mitochondria/mL). Interestingly, patients with GBM and VTE (n = 41) had a higher mitochondria concentration than patients with GBM without VTE (n = 41). In a murine model of inferior vena cava stenosis, intravenous delivery of mitochondria resulted in an increased rate of venous thrombosis compared with that in controls (70% and 28%, respectively). Mitochondria-induced venous thrombi were neutrophil-rich and contained more platelets than those in control thrombi. Furthermore, as mitochondria are the only source of cardiolipin in circulation, we compared the concentration of anticardiolipin immunoglobulin G in plasma samples of patients with GBM and found a higher concentration in patients with VTE (optical density, 0.69 ± 0.04) than in those without VTE (optical density, 0.51 ± 0.04). CONCLUSION: We concluded that mitochondria might play a role in the GBM-induced hypercoagulable state. We propose that quantifying circulating mitochondria or anticardiolipin antibody concentrations in patients with GBM might identify patients at increased risk of VTE.
Asunto(s)
Glioblastoma , Tromboembolia Venosa , Trombosis de la Vena , Animales , Ratones , Glioblastoma/complicaciones , Constricción Patológica/complicaciones , Factores de Riesgo , Trombosis de la Vena/complicacionesRESUMEN
INTRODUCTION: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. METHODS: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. RESULTS: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. CONCLUSIONS: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Pulmonares , Masculino , Femenino , Humanos , Neoplasias Pulmonares/genética , Aberraciones Cromosómicas , Carcinoma de Células Escamosas/genética , Estudios de Cohortes , Fumar/efectos adversosRESUMEN
INTRODUCTION: In recent years, the proportion of patients with NSCLC diagnosed at an early stage has increased continuously. METHODS: In this study, we analyzed samples and data collected from 119 samples from 67 early stage patients with NSCLC, including 52 pairs of tumor and adjacent non-neoplastic samples, and performed RNA-sequencing analysis with high sequencing depth. RESULTS: We found that immune-related genes were highly enriched among the differentially expressed genes and observed significantly higher inferred immune infiltration levels in adjacent non-neoplastic samples than in tumor samples. In survival analysis, the infiltration of certain immune cell types in tumor, but not adjacent non-neoplastic, samples were associated with overall patient survival, and excitingly, the differential infiltration between paired samples (tumor minus non-neoplastic) was more prognostic than expression in either non-neoplastic or tumor tissues. We also performed B cell receptor (BCR) and T cell receptor (TCR) repertoire analysis and observed more BCR/TCR clonotypes and increased BCR clonality in tumor than in non-neoplastic samples. Finally, we carefully quantified the fraction of the five histologic subtypes in our adenocarcinoma samples and found that higher histologic pattern complexity was associated with higher immune infiltration and low TCR clonality in the tumor-proximal regions. CONCLUSIONS: Our results indicated significantly differential immune characteristics between tumor and adjacent non-neoplastic samples and suggested that the two regions provided complementary prognostic values in early-stage NSCLCs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Pulmón/patología , Pronóstico , Receptores de Antígenos de Linfocitos T/genética , Microambiente Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
Differential methylation plays an important role in melanoma development and is associated with survival, progression and response to treatment. However, the mechanisms by which methylation promotes melanoma development are poorly understood. The traditional explanation of selective advantage provided by differential methylation postulates that hypermethylation of regulatory 5'-cytosine-phosphate-guanine-3' dinucleotides (CpGs) downregulates the expression of tumor suppressor genes and therefore promotes tumorigenesis. We believe that other (not necessarily alternative) explanations of the selective advantages of methylation are also possible. Here, we hypothesize that melanoma cells use methylation to shut down transcription of nonessential genes - those not required for cell survival and proliferation. Suppression of nonessential genes allows tumor cells to be more efficient in terms of energy and resource usage, providing them with a selective advantage over the tumor cells that transcribe and subsequently translate genes they do not need. We named the hypothesis the Rule Out (RO) hypothesis. The RO hypothesis predicts higher methylation of CpGs located in regulatory regions (CpG islands) of nonessential genes. It also predicts the higher methylation of regulatory CpGs linked to nonessential genes in melanomas compared to nevi and lower expression of nonessential genes in malignant (derived from melanoma) versus normal (derived from nonaffected skin) melanocytes. The analyses conducted using in-house and publicly available data found that all predictions derived from the RO hypothesis hold, providing observational support for the hypothesis.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Neoplasias Cutáneas/patología , Regiones Promotoras Genéticas , Metilación de ADN , Islas de CpG , Regulación Neoplásica de la Expresión Génica , Melanoma Cutáneo MalignoRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with a small risk of developing hematologic malignancies and a higher risk of cardiovascular diseases (CVD). We asked whether the reverse correlation exists and cardiometabolic risk factors have an impact on the progression of myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). We investigated the association between abnormal lipid profiles and inflammation in MDS, which shares many genetic mutations with CHIP, and the risk of developing acute leukemia. We examined the medical records of 11071 MDS patients. Among them, 5422 had at least one lipid profile or C-reactive protein (CRP) measurement. In univariate and multivariate analyses, elevated triglyceride and high-sensitive C-reactive protein (HS-CRP) were significantly associated with a diagnosis of acute leukemia in MDS patients. Next, we examined these associations in patients with available MDS prognostic scores (International Prognostic Scoring System, IPSS, or its revised version IPSS/R) (n = 2786 patients). We found that the statistical association between CRP and the progression of MDS to leukemia was independent of other variables in the scoring system. MDS patients with elevated CRP in both the high-risk and low-risk groups had a higher risk of progression to AML than those with a lower CRP. We speculate that inflammation might be a common denominator in developing hematologic malignancies and CVD in patients with clonal hematopoiesis.
RESUMEN
To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.
Asunto(s)
Estudio de Asociación del Genoma Completo , Neoplasias Pulmonares , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the number of potential sites for missense and nonsense mutations in individual transcripts and (ii) histology-specific nucleotide context-dependent mutation rates. To estimate mutation rates defined as the number of mutations per site per tumor we used silent mutations reported in the Catalog Of Somatic Mutations In Cancer (COSMIC). The estimates were nucleotide context dependent. We have identified 26 genes with an excess of missense and/or nonsense mutations for lung adenocarcinoma, 18 genes for small cell lung cancer, and 26 genes for squamous cell carcinoma of the lung. These genes include known genes and novel lung cancer gene candidates.
Asunto(s)
Codón sin Sentido , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Mutación Missense , Nucleótidos , OncogenesRESUMEN
OBJECTIVE: We undertook this study to examine the X chromosome complement in participants with systemic sclerosis (SSc) as well as idiopathic inflammatory myopathies. METHODS: The participants met classification criteria for the diseases. All participants underwent single-nucleotide polymorphism typing. We examined X and Y single-nucleotide polymorphism heterogeneity to determine the number of X chromosomes. For statistical comparisons, we used χ2 analyses with calculation of 95% confidence intervals. RESULTS: Three of seventy men with SSc had 47,XXY (P = 0.0001 compared with control men). Among the 435 women with SSc, none had 47,XXX. Among 709 men with polymyositis or dermatomyositis (PM/DM), seven had 47,XXY (P = 0.0016), whereas among the 1783 women with PM/DM, two had 47,XXX. Of 147 men with inclusion body myositis (IBM), six had 47,XXY, and 1 of the 114 women with IBM had 47,XXX. For each of these myositis disease groups, the excess 47,XXY and/or 47,XXX was significantly higher compared with in controls as well as the known birth rate of Klinefelter syndrome or 47,XXX. CONCLUSION: Klinefelter syndrome (47,XXY) is associated with SSc and idiopathic inflammatory myopathies, similar to other autoimmune diseases with type 1 interferon pathogenesis, namely, systemic lupus erythematosus and Sjögren syndrome.
RESUMEN
Genome wide association studies (GWASs) have identified tens of thousands of single nucleotide polymorphisms (SNPs) associated with human diseases and characteristics. A significant fraction of GWAS findings can be false positives. The gold standard for true positives is an independent validation. The goal of this study was to identify SNP features associated with validation success. Summary statistics from the Catalog of Published GWASs were used in the analysis. Since our goal was an analysis of reproducibility, we focused on the diseases/phenotypes targeted by at least 10 GWASs. GWASs were arranged in discovery-validation pairs based on the time of publication, with the discovery GWAS published before validation. We used four definitions of the validation success that differ by stringency. Associations of SNP features with validation success were consistent across the definitions. The strongest predictor of SNP validation was the level of statistical significance in the discovery GWAS. The magnitude of the effect size was associated with validation success in a non-linear manner. SNPs with risk allele frequencies in the range 30-70% showed a higher validation success rate compared to rarer or more common SNPs. Missense, 5'UTR, stop gained, and SNPs located in transcription factor binding sites had a higher validation success rate compared to intergenic, intronic and synonymous SNPs. There was a positive association between validation success and the level of evolutionary conservation of the sites. In addition, validation success was higher when discovery and validation GWASs targeted the same ethnicity. All predictors of validation success remained significant in a multivariate logistic regression model indicating their independent contribution. To conclude, we identified SNP features predicting validation success of GWAS hits. These features can be used to select SNPs for validation and downstream functional studies.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Secuencia Conservada , Etnicidad/genética , Frecuencia de los Genes , Estudios de Asociación Genética/métodos , Estudios de Asociación Genética/estadística & datos numéricos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Modelos Logísticos , Análisis Multivariante , Oportunidad Relativa , Grupos Raciales/genética , Reproducibilidad de los ResultadosRESUMEN
In drug development, preformulation is the key step, where compatibility between active pharmaceutical ingredient (API) and excipients is the crucial parameter. To simplify this process, reliable and suitable prediction models are needed. In this case, Hansen solubility parameters (HSPs) can be used. Moreover, HSPs can also describe and characterize the surface properties of the measured substances. Precisely, the surface properties of APIs and excipients affect the compatibility of the resulting dosage form. In this work, HSPs of six selected APIs of different chemical nature were determined (tadalafil, vardenafil-hydrochloride trihydrate, mefenamic acid, bisoprolol hemi-fumarate, meloxicam and indomethacin) using inverse gas chromatography (IGC) according to Snyder and Karger adsorption model. This study aimed to investigate the influence of APIs structure on HSPs and to prove the sensitivity of this method to different chemical nature of measured substances. Our results showed the influence of selected APIs chemical nature on HSPs. These results can provide a better understanding of API behaviour during the drug development process.
Asunto(s)
Excipientes , Indometacina , Cromatografía de Gases , Solubilidad , Propiedades de SuperficieRESUMEN
BACKGROUND: Breath analysis is a promising noninvasive technique that offers a wide range of opportunities to facilitate early diagnosis of lung cancer (LC). METHOD: Exhaled breath samples of 352 subjects including 160 with lung cancer (LC), 70 with benign pulmonary nodule (BPN) and 122 healthy controls (HC) were analyzed through thermal desorption coupled with gas chromatography-mass spectrometry (TD-GC-MS) to obtain the metabolic information from volatile organic compounds (VOCs). Statistical classification models were used to find diagnostic clusters of VOCs for the discrimination of HC, BPN and LC patients' early and advanced stages, as well as subtypes of LC. Receiver operator characteristics (ROC) curves with 5-fold validations were used to evaluate the accuracy of these models. RESULTS: The analysis revealed that 20, 19, 19, and 20 VOCs discriminated LC from HC, LC from BPN, histology and LC stages respectively. The calculated diagnostic indices showed a large area under the curve (AUC) to distinguish HC from LC (AUC: 0.987, 95 % confidence interval (CI): 0.976-0.997), BPN from LC (AUC: 0.809, 95 % CI: 0.758-0.860), NSCLC from SCLC (AUC: 0.939, 95 % CI: 0.875-0.995) and Stage III from stage III-IV (AUC: 0.827, 95 % CI: 0.768-0.886). The comparison between the high-risk groups (BPN and HC smokers) and early stages LC resulted in the AUC of 0.756 (95 %CI: 0.681-0.817) for BPN vs. early stage LC and AUC of 0.986 (95 % CI: 0.972-0.994) for HC smoker vs. early stage LC. CONCLUSION: Volatome of breath of the LC patients was significantly different from that of both BPN patients and HC and showed an ability of distinguishing early from advance stage LC and NSCLC from SCLC. We conclude that the volatome has a potential to help improve early diagnosis of LC.
Asunto(s)
Neoplasias Pulmonares , Compuestos Orgánicos Volátiles , Pruebas Respiratorias , Detección Precoz del Cáncer , Espiración , Humanos , Neoplasias Pulmonares/diagnósticoRESUMEN
BACKGROUND: The smoking behavior of American Indians (AI) differs from that of non-Hispanic whites (NHW). Typically light smokers, cessation interventions in AIs are generally less effective. To develop more effective cessation programs for AIs, clinicians, researchers, and public health workers need a better understanding of the genetic factors involved in their smoking behavior. Our aim was to assess whether SNPs associated with smoking behavior in NHWs are also associated with smoking in AIs. METHODS: We collected questionnaire data on smoking behaviors and analyzed blood and saliva samples from two Tribal populations with dramatically different cultures and smoking prevalence, one in the Northern Plains (n = 323) and the other in the Southwest (n = 176). A total of 384 SNPs were genotyped using an Illumina custom GoldenGate platform. Samples were also assessed for cotinine and 3-hydroxycotinine as markers of nicotine intake and nicotine metabolite ratio. RESULTS: Among 499 participants, we identified, in the Northern Plains sample only, a variant of the gamma-aminobutyric acid receptor subunit alpha-2 (GABRA2) (rs2119767) on chromosome 4p that was associated with many of the intake biomarkers of smoking we examined, suggesting a role for this gene in modifying smoking behavior in this population. We also identified three SNPs, in the Southwest sample only, as significant correlates of only cigarettes per day: rs4274224, rs4245147 (both dopamine receptor D2 gene), and rs1386493 (tryptophan hydroxylase 2 gene). CONCLUSIONS: The contribution of many genes known to underlie smoking behaviors in NHWs may differ in AIs. IMPACT: Once validated, these variants could be useful in developing more effective cessation strategies.
Asunto(s)
Fumar/epidemiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto Joven , Indio Americano o Nativo de AlaskaRESUMEN
We hypothesized that human genes differ by their sensitivity to ultraviolet (UV) exposure. We used somatic mutations detected by genome-wide screens in melanoma and reported in the Catalog Of Somatic Mutations In Cancer. As a measure of UV sensitivity, we used the number of silent mutations generated by C>T transitions in pyrimidine dimers of a given transcript divided by the number of potential sites for this type of mutations in the transcript. We found that human genes varied by UV sensitivity by two orders of magnitude. We noted that the melanoma-associated tumor suppressor gene CDKN2A was among the top five most UV-sensitive genes in the human genome. Melanoma driver genes have a higher UV-sensitivity compared with other genes in the human genome. The difference was more prominent for tumor suppressors compared with oncogene. The results of this study suggest that differential sensitivity of human transcripts to UV light may explain melanoma specificity of some driver genes. Practical significance of the study relates to the fact that differences in UV sensitivity among human genes need to be taken into consideration whereas predicting melanoma-associated genes by the number of somatic mutations detected in a given gene.
Asunto(s)
Melanoma , Neoplasias Cutáneas , Genoma Humano , Humanos , Melanoma/genética , Mutación , Oncogenes , Mutación Silenciosa , Neoplasias Cutáneas/genética , Rayos UltravioletaRESUMEN
We hypothesized that a joint analysis of cancer risk-associated single-nucleotide polymorphism (SNP) and somatic mutations in tumor samples can predict functional and potentially causal SNPs from GWASs. We used mutations reported in the Catalog of Somatic Mutations in Cancer (COSMIC). Confirmed somatic mutations were subdivided into two groups: (1) mutations reported as SNPs, which we call mutational/SNPs and (2) somatic mutations that are not reported as SNPs, which we call mutational/noSNPs. It is generally accepted that the number of times a somatic mutation is reported in COSMIC correlates with its selective advantage to tumors, with more frequently reported mutations being more functional and providing a stronger selective advantage to the tumor cell. We found that mutations reported ≥10 times in COSMIC-frequent mutational/SNPs (fmSNPs) are likely to be functional. We identified 12 cancer risk-associated SNPs reported in the Catalog of published GWASs at least 10 times as confirmed somatic mutations and therefore deemed to be functional. Additionally, we have identified 42 SNPs that are tightly linked (R2 ≥ 0.8) to SNPs reported in the Catalog of published GWASs as cancer risk associated and that are also reported as fmSNPs. As a result, 54 candidate functional/potentially causal cancer risk associated SNPs were identified. We found that fmSNPs are more likely to be located in evolutionarily conserved regions compared with cancer risk associated SNPs that are not fmSNPs. We also found that fmSNPs also underwent positive selection, which can explain why they exist as population polymorphisms.
Asunto(s)
Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias/epidemiología , Neoplasias/genética , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma Completo , Humanos , RiesgoRESUMEN
Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10-15) and replication (adjusted OR = 2.93, P = 2.22 × 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
Asunto(s)
Adenocarcinoma/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Neoplasias Pulmonares/genética , Anciano , Alelos , Bases de Datos Genéticas , Femenino , Predisposición Genética a la Enfermedad , Técnicas de Genotipaje , Mutación de Línea Germinal , Heterocigoto , Humanos , Judíos/genética , Masculino , Persona de Mediana Edad , Mutación Missense , Oportunidad Relativa , Análisis de Secuencia por Matrices de Oligonucleótidos , Linaje , RNA-Seq , Factores de Riesgo , Población Blanca/genéticaRESUMEN
BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. RESULTS: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10-6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10-3). CONCLUSIONS: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. IMPACT: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Estudio de Asociación del Genoma Completo/métodos , Neoplasias Pulmonares/genética , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Over the relatively short history of Genome Wide Association Studies (GWASs), hundreds of GWASs have been published and thousands of disease risk-associated SNPs have been identified. Summary statistics from the conducted GWASs are often available and can be used to identify SNP features associated with the level of GWAS statistical significance. Those features could be used to select SNPs from gray zones (SNPs that are nominally significant but do not reach the genome-wide level of significance) for targeted analyses. METHODS: We used summary statistics from recently published breast and lung cancer and scleroderma GWASs to explore the association between the level of the GWAS statistical significance and the expression quantitative trait loci (eQTL) status of the SNP. Data from the Genotype-Tissue Expression Project (GTEx) were used to identify eQTL SNPs. RESULTS: We found that SNPs reported as eQTLs were more significant in GWAS (higher -log10p) regardless of the tissue specificity of the eQTL. Pan-tissue eQTLs (those reported as eQTLs in multiple tissues) tended to be more significant in the GWAS compared to those reported as eQTL in only one tissue type. eQTL density in the ±5 kb adjacent region of a given SNP was also positively associated with the level of GWAS statistical significance regardless of the eQTL status of the SNP. We found that SNPs located in the regions of high eQTL density were more likely to be located in regulatory elements (transcription factor or miRNA binding sites). When SNPs were stratified by the level of statistical significance, the proportion of eQTLs was positively associated with the mean level of statistical significance in the group. The association curve reaches a plateau around -log10p ≈ 5. The observed associations suggest that quasi-significant SNPs (10- 5 < p < 5 × 10- 8) and SNPs at the genome wide level of statistical significance (p < 5 × 10- 8) may have a similar proportions of risk associated SNPs. CONCLUSIONS: The results of this study indicate that the SNP's eQTL status, as well as eQTL density in the adjacent region are positively associated with the level of statistical significance of the SNP in GWAS.