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1.
Artigo em Inglês | MEDLINE | ID: mdl-35027437

RESUMO

INTRODUCTION: Somatic EGFR mutations define a subset of non-small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiological datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiological datasets and evaluated the clinical utility of these approaches. METHODS: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiological datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cutpoint, and a second epidemiological, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. RESULTS: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance-index of 0.75 (95%CI: 0.74-0.77) in the training and 0.77 (95%CI: 0.74-0.79) in the testing dataset. At an optimal cut-point of probability-score=0.335, sensitivity=69% and specificity=72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of NSCLC patients, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. CONCLUSION: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. IMPACT: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34964002

RESUMO

PURPOSE: Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete. MATERIALS AND METHODS: We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases. RESULTS: In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant. CONCLUSION: These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.

3.
J Invest Dermatol ; 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34813871

RESUMO

Genome-wide association studies (GWAS) have identified a number of risk loci for cutaneous melanoma. Cutaneous melanoma shares overlapping genetic risk (genetic correlation) with a number of other traits, including with its risk factors such as sunburn propensity. This genetic correlation can be exploited to identify additional cutaneous melanoma risk loci by multi-trait analysis of GWAS (MTAG). We used bivariate LD-score regression to identify traits that are genetically correlated with clinically-confirmed cutaneous melanoma, and then used publicly available GWAS for these traits in a MTAG. MTAG allows GWAS to be combined while accounting for sample overlap and incomplete genetic correlation. We identified a total of 74 genome-wide independent loci; 19 of them were not previously reported in the input cutaneous melanoma GWAS-meta-analysis. 55 of these loci were replicated (P < 0.05/74), Bonferroni corrected P -value in two independent cutaneous melanoma replication cohorts from Melanoma Institute Australia and 23andMe, Inc. Among the new cutaneous melanoma loci are ones that have also been associated with autoimmune traits including rs715199 near LPP, and rs10858023 near AP4B1. Our analysis indicates genetic correlation between traits can be leveraged to identify new risk genes for cutaneous melanoma.

4.
J Pathol Clin Res ; 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34618413

RESUMO

The tumor microenvironment (TME), including immune cells, cancer-associated fibroblasts, endothelial cells, adjacent normal cells, and others, plays a crucial role in influencing tumor behavior and progression. Here, we characterized the TME in 83 primary renal tumors and matched metastatic or recurrence tissue samples (n = 15) from papillary renal cell carcinoma (pRCC) types 1 (n = 20) and 2 (n = 49), collecting duct carcinomas (CDC; n = 14), and high-grade urothelial carcinomas (HGUC; n = 5). We investigated 10 different markers of immune infiltration, vasculature, cell proliferation, and epithelial-to-mesenchymal transition by using machine learning image analysis in conjunction with immunohistochemistry. Marker expression was compared by Mann-Whitney and Kruskal-Wallis tests and correlations across markers using Spearman's rank correlation coefficient. Multivariable Poisson regression analysis was used to compare marker expression between histological types, while accounting for variation in tissue size. Several immune markers showed different rates of expression across histological types of renal carcinoma. Using pRCC1 as reference, the incidence rate ratio (IRR) of CD3+ T cells (IRR [95% confidence interval, CI] = 2.48 [1.53-4.01]) and CD20+ B cells (IRR [95% CI] = 4.38 [1.22-5.58]) was statistically significantly higher in CDC. In contrast, CD68+ macrophages predominated in pRCC1 (IRR [95% CI] = 2.35 [1.42-3.9]). Spatial analysis revealed CD3+ T-cell and CD20+ B-cell expressions in CDC to be higher at the proximal (p < 0.0001) and distal (p < 0.0001) tumor periphery than within the central tumor core. In contrast, expression of CD68+ macrophages in pRCC2 was higher in the tumor center compared to the proximal (p = 0.0451) tumor periphery and pRCC1 showed a distance-dependent reduction, from the central tumor, in CD68+ macrophages with the lowest expression of CD68 marker at the distal tumor periphery (p = 0.004). This study provides novel insights into the TME of rare kidney cancer types, which are often understudied. Our findings of differences in marker expression and localization by histological subtype could have implications for tumor progression and response to immunotherapies or other targeted therapies.

5.
J Am Stat Assoc ; 116(533): 133-143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34483403

RESUMO

Large-scale genome-wide association (GWAS) studies provide opportunities for developing genetic risk prediction models that have the potential to improve disease prevention, intervention or treatment. The key step is to develop polygenic risk score (PRS) models with high predictive performance for a given disease, which typically requires a large training data set for selecting truly associated single nucleotide polymorphisms (SNPs) and estimating effect sizes accurately. Here, we develop a comprehensive penalized regression for fitting l 1 regularized regression models to GWAS summary statistics. We propose incorporating Pleiotropy and ANnotation information into PRS (PANPRS) development through suitable formulation of penalty functions and associated tuning parameters. Extensive simulations show that PANPRS performs equally well or better than existing PRS methods when no functional annotation or pleiotropy is incorporated. When functional annotation data and pleiotropy are informative, PANPRS substantially outperforms existing PRS methods in simulations. Finally, we applied our methods to build PRS for type 2 diabetes and melanoma and found that incorporating relevant functional annotations and GWAS of genetically related traits improved prediction of these two complex diseases.

6.
Am J Hum Genet ; 108(9): 1611-1630, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34343493

RESUMO

Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma de Células Escamosas/genética , Cromossomos Humanos Par 7 , Loci Gênicos , Melanócitos/metabolismo , Melanoma/genética , Receptores de Hidrocarboneto Arílico/genética , Neoplasias Cutâneas/genética , Alelos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Cromatina/química , Cromatina/metabolismo , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanócitos/efeitos da radiação , Melanoma/metabolismo , Melanoma/patologia , Dibenzodioxinas Policloradas/toxicidade , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Regiões Promotoras Genéticas , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Banho de Sol , Raios Ultravioleta/efeitos adversos
7.
J Natl Cancer Inst ; 2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34402912

RESUMO

BACKGROUND: Immune cell transcriptome signatures have been widely used to study the lung tumor microenvironment (TME). However, it is unclear to what extent the immune cell composition in the lung TME varies across histological and molecular subtypes (inter-tumor heterogeneity or Inter-TH) and within tumors (intratumor heterogeneity or ITH), and whether ITH has any prognostic relevance. METHODS: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients we quantified the Inter-TH of immune gene expression and immune cell abundance and evaluated the association of median immune cell abundance with clinical/pathological features and overall survival. In 39 tumors with 132 multi-region samples, we also analyzed the ITH of immune cell abundance in relation to overall survival using a variance-weighted multivariate Cox model not biased by the number of samples per tumor. RESULTS: Substantial Inter-TH of 14 immune cell types was observed even within the same histological and molecular subtypes, but early-stage tumors had higher lymphocyte infiltration across all tumor types. In multi-region samples, an unbiased estimate of low ITH of overall immune cell composition (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002) and macrophages (HR = 0.50, 95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The ITH of three markers, including CD163 and CD68 (macrophages) and CCL13 (dendritic cells), was enough to characterize the ITH of the corresponding immune cell abundances and its association with overall survival. CONCLUSION: This study suggests that lack of immune cell diversity may facilitate tumor evasion and progression. ITH inferred from CCL13, CD163 and CD68 could be used as a prognostic tool in clinical practice.

8.
Clin Genitourin Cancer ; 19(5): e280-e285, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34362694

RESUMO

INTRODUCTION: The optimal length for clinical follow-up of renal cell carcinoma (RCC) patients is unclear. We evaluated the impact of ISUP/WHO tumor grade and histological subtype on short- and long-term survival and risk of recurrence/metastasis in a large cohort of RCC patients. PATIENTS AND METHODS: We studied 1679 RCC patients from a single referral center in Italy. Adjusted hazard ratios for overall survival were estimated using Cox regression models. Adjusted absolute risk of developing recurrence or metastasis was computed considering competing risks of mortality. RESULTS: During up to 13 years of follow-up, 175 (10.4%) RCC patients died, of whom 92% beyond 5 years. Hazard ratio of grade IV clear cell carcinomas (ccRCC) was 3.82 compared to grade II. Notably, 33% of recurrences and 56% of distant metastases occurred beyond 5 years of follow-up. The estimated probabilities of recurrence/metastasis were 15% and 45% within and beyond 5 years of follow-up, respectively. After 5 years, the absolute risk of recurrences increased also for papillary renal cell carcinoma type I (35.2%) and grade I ccRCC (17%). CONCLUSION: After 5 years of follow-up, both risk of mortality and recurrences or metastases were high and were modified by histological types and tumor grade. These data strongly support histology- and grade-tailored surveillance strategies and long-term follow-up for RCC patients.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Estudos de Coortes , Seguimentos , Humanos , Recidiva Local de Neoplasia
9.
Am J Hum Genet ; 108(9): 1631-1646, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34293285

RESUMO

Although expression quantitative trait loci (eQTLs) have been powerful in identifying susceptibility genes from genome-wide association study (GWAS) findings, most trait-associated loci are not explained by eQTLs alone. Alternative QTLs, including DNA methylation QTLs (meQTLs), are emerging, but cell-type-specific meQTLs using cells of disease origin have been lacking. Here, we established an meQTL dataset by using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization with meQTLs, eQTLs, and mRNA splice-junction QTLs from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified candidate susceptibility genes at 63% of melanoma GWAS loci. Among the three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes is preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTLs and melanoma meQTLs identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTLs identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIP-seq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTLs.


Assuntos
Redes Reguladoras de Genes , Fatores Reguladores de Interferon/genética , Melanócitos/metabolismo , Melanoma/genética , Locos de Características Quantitativas , Neoplasias Cutâneas/genética , Alelos , Atlas como Assunto , Cromatina/química , Cromatina/metabolismo , Mapeamento Cromossômico , Metilação de DNA , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Fatores Reguladores de Interferon/metabolismo , Masculino , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Cultura Primária de Células , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transcriptoma
10.
Fam Cancer ; 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34215961

RESUMO

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.

11.
Am J Epidemiol ; 190(9): 1948-1960, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33942053

RESUMO

Evaluating gene by environment (G × E) interaction under an additive risk model (i.e., additive interaction) has gained wider attention. Recently, statistical tests have been proposed for detecting additive interaction, utilizing an assumption on gene-environment (G-E) independence to boost power, that do not rely on restrictive genetic models such as dominant or recessive models. However, a major limitation of these methods is a sharp increase in type I error when this assumption is violated. Our goal was to develop a robust test for additive G × E interaction under the trend effect of genotype, applying an empirical Bayes-type shrinkage estimator of the relative excess risk due to interaction. The proposed method uses a set of constraints to impose the trend effect of genotype and builds an estimator that data-adaptively shrinks an estimator of relative excess risk due to interaction obtained under a general model for G-E dependence using a retrospective likelihood framework. Numerical study under varying levels of departures from G-E independence shows that the proposed method is robust against the violation of the independence assumption while providing an adequate balance between bias and efficiency compared with existing methods. We applied the proposed method to the genetic data of Alzheimer disease and lung cancer.


Assuntos
Teorema de Bayes , Interação Gene-Ambiente , Genótipo , Doença de Alzheimer/etiologia , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Pesquisa Empírica , Predisposição Genética para Doença/genética , Humanos , Funções Verossimilhança , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Modelos Estatísticos , Polimorfismo de Nucleotídeo Único/genética , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos
12.
Scand J Work Environ Health ; 47(6): 475-481, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33942106

RESUMO

OBJECTIVES: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer. METHODS: In 13 case-control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices. RESULTS: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51)] and women [PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45)], but not PSI. CONCLUSIONS: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.

13.
PLoS Genet ; 17(3): e1009254, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33667223

RESUMO

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta<5x10-8) aerodigestive SqCC susceptibility loci in the 2q33.1 region (rs56321285, TMEM273). Additionally, three previously unknown loci reached suggestive significance (Pmeta<5x10-7): 1q32.1 (rs12133735, near MDM4), 5q31.2 (rs13181561, TMEM173) and 19p13.11 (rs61494113, ABHD8). Multiple previously identified loci for aerodigestive SqCC also showed evidence of pleiotropy in at least another SqCC site, these include: 4q23 (ADH1B), 6p21.33 (STK19), 6p21.32 (HLA-DQB1), 9p21.33 (CDKN2B-AS1) and 13q13.1(BRCA2). Gene-based association and gene set enrichment identified a set of 48 SqCC-related genes rel to DNA damage and epigenetic regulation pathways. Our study highlights the importance of cross-cancer analyses to identify pleiotropic risk loci of histology-related cancers arising at distinct anatomical sites.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias do Sistema Digestório/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alelos , Biomarcadores Tumorais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/patologia , Genótipo , Humanos , Razão de Chances , Transdução de Sinais
14.
Am J Epidemiol ; 190(6): 962-976, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33712835

RESUMO

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.


Assuntos
Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Neoplasias Pulmonares/genética , Medição de Risco/métodos , Sequenciamento Completo do Genoma/métodos , Causalidade , Humanos , Estudos Retrospectivos , Fatores de Risco
15.
Cancer Res ; 81(6): 1607-1615, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33472890

RESUMO

Lung cancer is the leading cause of cancer-related death globally. An improved risk stratification strategy can increase efficiency of low-dose CT (LDCT) screening. Here we assessed whether individual's genetic background has clinical utility for risk stratification in the context of LDCT screening. On the basis of 13,119 patients with lung cancer and 10,008 controls with European ancestry in the International Lung Cancer Consortium, we constructed a polygenic risk score (PRS) via 10-fold cross-validation with regularized penalized regression. The performance of risk model integrating PRS, including calibration and ability to discriminate, was assessed using UK Biobank data (N = 335,931). Absolute risk was estimated on the basis of age-specific lung cancer incidence and all-cause mortality as competing risk. To evaluate its potential clinical utility, the PRS distribution was simulated in the National Lung Screening Trial (N = 50,772 participants). The lung cancer ORs for individuals at the top decile of the PRS distribution versus those at bottom 10% was 2.39 [95% confidence interval (CI) = 1.92-3.00; P = 1.80 × 10-14] in the validation set (P trend = 5.26 × 10-20). The OR per SD of PRS increase was 1.26 (95% CI = 1.20-1.32; P = 9.69 × 10-23) for overall lung cancer risk in the validation set. When considering absolute risks, individuals at different PRS deciles showed differential trajectories of 5-year and cumulative absolute risk. The age reaching the LDCT screening recommendation threshold can vary by 4 to 8 years, depending on the individual's genetic background, smoking status, and family history. Collectively, these results suggest that individual's genetic background may inform the optimal lung cancer LDCT screening strategy. SIGNIFICANCE: Three large-scale datasets reveal that, after accounting for risk factors, an individual's genetics can affect their lung cancer risk trajectory, thus may inform the optimal timing for LDCT screening.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Pulmonares/epidemiologia , Modelos Genéticos , Herança Multifatorial , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Detecção Precoce de Câncer/normas , Detecção Precoce de Câncer/estatística & dados numéricos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Incidência , Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/prevenção & controle , Aprendizado de Máquina , Masculino , Programas de Rastreamento/normas , Programas de Rastreamento/estatística & dados numéricos , Anamnese , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Guias de Prática Clínica como Assunto , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Fumar/epidemiologia , Tomografia Computadorizada por Raios X/normas , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Reino Unido/epidemiologia
16.
Occup Environ Med ; 78(4): 269-278, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33115922

RESUMO

OBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.


Assuntos
Neoplasias Pulmonares/induzido quimicamente , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional/efeitos adversos , Pintura/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Fumar/epidemiologia
17.
Int J Cancer ; 148(5): 1077-1086, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-32914876

RESUMO

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10-4 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (ORMVMR = 1.28, 95% CI = 1.06-1.55, PMVMR = .011), and an inverse effect on lung adenocarcinoma (ORMVMR = 0.86, 95% CI = 0.77-0.96, PMVMR = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (ORUVMR = 1.19, 95% CI = 1.01-1.40, PUVMR = .036), but this effect disappeared after adjustment of smoking (ORMVMR = 1.02, 95% CI = 0.90-1.16, PMVMR = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.


Assuntos
Índice de Massa Corporal , Neoplasias Pulmonares/etiologia , Análise da Randomização Mendeliana/métodos , Fumar/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Obesidade/complicações , Polimorfismo de Nucleotídeo Único
18.
Front Med ; 15(2): 275-291, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32889700

RESUMO

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Heterogeneidade Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único
19.
Autophagy ; 16(12): 2276-2281, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33249989

RESUMO

In less than eleven months, the world was brought to a halt by the COVID-19 outbreak. With hospitals becoming overwhelmed, one of the highest priorities concerned critical care triage to ration the scarce resources of intensive care units. Which patient should be treated first? Based on what clinical and biological criteria? A global joint effort rapidly led to sequencing the genomes of tens of thousands of COVID-19 patients to determine the patients' genetic signature that causes them to be at risk of suddenly developing severe disease. In this commentary, we would like to consider some points concerning the use of a multifactorial risk score for COVID-19 severity. This score includes macroautophagy (hereafter referred to as autophagy), a critical host process that controls all steps harnessed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Abbreviation list: ATG5: autophagy related 5; BECN1: beclin 1; COVID-19: coronavirus infectious disease-2019; EGR1: early growth response 1; ER: endoplasmic reticulum; DMVs: double-membrane vesicles; IBV: infectious bronchitis virus; MAP1LC3: microtubule associated protein 1 light chain 3; LC3-I: proteolytically processed, non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; MEFs: mouse embryonic fibroblasts; MERS-CoV: Middle East respiratory syndrome-coronavirus; MHV: mouse hepatitis virus; NSP: non-structural protein; PEDV: porcine epidemic diarrhea virus; PLP2-TM: membrane-associated papain-like protease 2; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TGEV: transmissible gastroenteritis virus.


Assuntos
Proteínas Relacionadas à Autofagia/genética , Autofagia/genética , COVID-19/diagnóstico , COVID-19/terapia , Transcriptoma , Animais , Autofagia/fisiologia , Proteínas Relacionadas à Autofagia/análise , Biomarcadores/análise , Biomarcadores/metabolismo , COVID-19/genética , COVID-19/patologia , Predisposição Genética para Doença , Humanos , Vírus da Bronquite Infecciosa/fisiologia , Camundongos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Técnicas de Diagnóstico Molecular/métodos , Prognóstico , Projetos de Pesquisa , Fatores de Risco , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Transcriptoma/fisiologia
20.
Cancers (Basel) ; 12(11)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198197

RESUMO

Collecting duct carcinoma (CDC) is rare and aggressive histology of kidney cancers. Although different therapeutic approaches have been tested, the 2-year survival remains very poor. Since CDC exhibits overlapping features with urothelial carcinoma, the analysis of shared molecular alterations could provide new insights into the understanding of this rare disease and also therapeutic options. We collected 26 CDC cases, and we assessed HER2 protein expression by immunohistochemistry (IHC) and gene amplification by fluorescence in-situ hybridization (FISH) according to 2018 ASCO/CAP HER2-testing recommendations. Six out of twenty-six (23%) tumors showed HER2 positive staining. In particular, 3+ score was present in 2/6 cases (33%), 2+ in 3/6 cases (50%) and 1+ in 1/6 cases (17%). The 6 HER2+ tumors were also analyzed by FISH to assess gene copy number. One out of six CDC with IHC 3+ was also HER2 amplified, showing an average HER2 copy number ≥4.0 (10.85) and a HER2/CEP17 ratio ≥ (5.63), while the 5/6 cases were HER2 negative. Based on the 2018 ASCO/CAP guidelines overall, 2/26 CDC cases (8%) were HER2+. The present study provides evidence for testing, in future studies, HER2 to assess its clinical value as a novel target for the treatment of this highly malignant cancer.

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