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1.
PLoS Genet ; 17(3): e1009254, 2021 Mar.
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.

2.
Genet Epidemiol ; 44(8): 924-933, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32710482

RESUMO

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

3.
NAR Genom Bioinform ; 2(2): lqaa021, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32363341

RESUMO

The emergence of next-generation sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations, such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analysing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub platform: https://github.com/IARCbioinfo/needlestack.

4.
JCO Glob Oncol ; 6: 486-499, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32213095

RESUMO

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) incidence is high in South America, where recent data on survival are sparse. We investigated the main predictors of HNSCC survival in Brazil, Argentina, Uruguay, and Colombia. METHODS: Sociodemographic and lifestyle information was obtained from standardized interviews, and clinicopathologic data were extracted from medical records and pathologic reports. The Kaplan-Meier method and Cox regression were used for statistical analyses. RESULTS: Of 1,463 patients, 378 had a larynx cancer (LC), 78 hypopharynx cancer (HC), 599 oral cavity cancer (OC), and 408 oropharynx cancer (OPC). Most patients (55.5%) were diagnosed with stage IV disease, ranging from 47.6% for LC to 70.8% for OPC. Three-year survival rates were 56.0% for LC, 54.7% for OC, 48.0% for OPC, and 37.8% for HC. In multivariable models, patients with stage IV disease had approximately 7.6 (LC/HC), 11.7 (OC), and 3.5 (OPC) times higher mortality than patients with stage I disease. Current and former drinkers with LC or HC had approximately 2 times higher mortality than never-drinkers. In addition, older age at diagnosis was independently associated with worse survival for all sites. In a subset analysis of 198 patients with OPC with available human papillomavirus (HPV) type 16 data, those with HPV-unrelated OPC had a significantly worse 3-year survival compared with those with HPV-related OPC (44.6% v 75.6%, respectively), corresponding to a 3.4 times higher mortality. CONCLUSION: Late stage at diagnosis was the strongest predictor of lower HNSCC survival. Early cancer detection and reduction of harmful alcohol use are fundamental to decrease the high burden of HNSCC in South America.

5.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31231134

RESUMO

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.


Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Biologia Computacional , Feminino , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores Sexuais
6.
Mol Genet Genomic Med ; 7(6): e707, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31066241

RESUMO

BACKGROUND: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. METHODS: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. RESULTS: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). CONCLUSION: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.


Assuntos
Aldeído-Desidrogenase Mitocondrial/genética , Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Consumo de Bebidas Alcoólicas/epidemiologia , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/epidemiologia , Feminino , Interação Gene-Ambiente , Humanos , Pessoa de Meia-Idade
7.
PLoS Med ; 16(1): e1002724, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605491

RESUMO

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.


Assuntos
Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Obesidade/complicações , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Carcinoma de Células Renais/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Neoplasias Renais/genética , Lipídeos/sangue , Masculino , Análise da Randomização Mendeliana , Obesidade/genética , Fatores de Risco
9.
Carcinogenesis ; 39(9): 1135-1140, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-29924316

RESUMO

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.


Assuntos
Adenocarcinoma/genética , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 9/genética , Humanos , Pulmão/patologia , Anamnese , Polimorfismo de Nucleotídeo Único/genética
10.
Sci Rep ; 8(1): 4534, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29540730

RESUMO

With the aim to dissect the effect of adult height on head and neck cancer (HNC), we use the Mendelian randomization (MR) approach to test the association between genetic instruments for height and the risk of HNC. 599 single nucleotide polymorphisms (SNPs) were identified as genetic instruments for height, accounting for 16% of the phenotypic variation. Genetic data concerning HNC cases and controls were obtained from a genome-wide association study. Summary statistics for genetic association were used in complementary MR approaches: the weighted genetic risk score (GRS) and the inverse-variance weighted (IVW). MR-Egger regression was used for sensitivity analysis and pleiotropy evaluation. From the GRS analysis, one standard deviation (SD) higher height (6.9 cm; due to genetic predisposition across 599 SNPs) raised the risk for HNC (Odds ratio (OR), 1.14; 95% Confidence Interval (95%CI), 0.99-1.32). The association analyses with potential confounders revealed that the GRS was associated with tobacco smoking (OR = 0.80, 95% CI (0.69-0.93)). MR-Egger regression did not provide evidence of overall directional pleiotropy. Our study indicates that height is potentially associated with HNC risk. However, the reported risk could be underestimated since, at the genetic level, height emerged to be inversely associated with smoking.


Assuntos
Estatura/genética , Neoplasias de Cabeça e Pescoço/genética , Análise da Randomização Mendeliana/métodos , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade
11.
Int J Cancer ; 143(1): 32-44, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29405297

RESUMO

Head and neck cancer (HNC) is a preventable malignancy that continues to cause substantial morbidity and mortality worldwide. Using data from the ARCAGE and Rome studies, we investigated the main predictors of survival after larynx, hypopharynx and oral cavity (OC) cancers. We used the Kaplan-Meier method to estimate overall survival, and Cox proportional models to examine the relationship between survival and sociodemographic and clinical characteristics. 604 larynx, 146 hypopharynx and 460 OC cancer cases were included in this study. Over a median follow-up time of 4.6 years, nearly 50% (n = 586) of patients died. Five-year survival was 65% for larynx, 55% for OC and 35% for hypopharynx cancers. In a multivariable analysis, we observed an increased mortality risk among older (≥71 years) versus younger (≤50 years) patients with larynx/hypopharynx combined (LH) and OC cancers [HR = 1.61, 95% CI 1.09-2.38 (LH) and HR = 2.12, 95% CI 1.35-3.33 (OC)], current versus never smokers [HR = 2.67, 95% CI 1.40-5.08 (LH) and HR = 2.16, 95% CI 1.32-3.54 (OC)] and advanced versus early stage disease at diagnosis [IV versus I, HR = 2.60, 95% CI 1.78-3.79 (LH) and HR = 3.17, 95% CI 2.05-4.89 (OC)]. Survival was not associated with sex, alcohol consumption, education, oral health, p16 expression, presence of HPV infection or body mass index 2 years before cancer diagnosis. Despite advances in diagnosis and therapeutic modalities, survival after HNC remains low in Europe. In addition to the recognized prognostic effect of stage at diagnosis, smoking history and older age at diagnosis are important prognostic indicators for HNC.


Assuntos
Neoplasias Hipofaríngeas/mortalidade , Neoplasias Laríngeas/mortalidade , Neoplasias Bucais/mortalidade , Fumar/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Europa (Continente)/epidemiologia , Feminino , Humanos , Neoplasias Hipofaríngeas/patologia , Neoplasias Laríngeas/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Estadiamento de Neoplasias , Análise de Regressão , Fumar/efeitos adversos , Análise de Sobrevida
12.
J Natl Cancer Inst ; 109(9)2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28954281

RESUMO

Background: Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. Methods: We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses. Results: Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias. Conclusions: Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Metabolismo Energético , Obesidade/complicações , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Insulina/metabolismo , Resistência à Insulina , Funções Verossimilhança , Masculino , Razão de Chances , Neoplasias Pancreáticas/epidemiologia , Polimorfismo de Nucleotídeo Único , Vigilância da População , Característica Quantitativa Herdável , Fatores de Risco
13.
Eur Urol ; 72(5): 747-754, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28797570

RESUMO

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13). CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk. PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.


Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Telômero/genética , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Leucócitos/química , Análise da Randomização Mendeliana , Razão de Chances , Fenótipo , Medição de Risco , Fatores de Risco , Telômero/patologia
15.
Nat Commun ; 8: 15724, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28598434

RESUMO

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.


Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
16.
PLoS One ; 12(5): e0177775, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28505207

RESUMO

A small proportion of women who are exposed to infection with human-papillomavirus (HPV) develop cervical cancer (CC). Genetic factors may affect the risk of progression from HPV infection to cervical precancer and cancer. We used samples from the International Agency for Research on Cancer (IARC) multicentric case-control study to evaluate the association of selected genetic variants with CC. Overall, 790 CC cases and 717 controls from Algeria, Morocco, India and Thailand were included. Cervical exfoliated cells were obtained from control women and cervical exfoliated cells or biopsy specimens from cases. HPV-positivity was determined using a general primer GP5+/6+ mediated PCR. Unconditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) of host genotypes with CC risk, using the homozygous wild type genotype as the referent category and adjusting by age and study centre. The association of polymorphisms with the risk of high-risk HPV-positivity among controls was also evaluated. A statistically significant association was observed between single nucleotide polymorphism (SNP) CHR6 rs2844511 and CC risk: the OR for carriers of the GA or GG genotypes was 0.70 (95% CI: 0.43-1.14) and 0.61 (95% CI: 0.38-0.98), respectively, relative to carriers of AA genotype (p-value for trend 0.03). We also observed associations of borderline significance with the TIPARP rs2665390 polymorphism, which was previously found to be associated with ovarian and breast cancer, and with the EXOC1 rs13117307 polymorphism, which has been linked to cervical cancer in a large study in a Chinese population. We confirmed the association between CC and the rs2844511 polymorphism previously identified in a GWAS study in a Swedish population. The major histocompatibility region of chromosome 6, or perhaps other SNPs in linkage disequilibrium, may be involved in CC onset.

18.
Chin J Cancer ; 36(1): 3, 2017 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-28063457

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a commonly diagnosed cancer in Southeast Asia. Many studies have examined the risk factors for NPC, yet the roles of some risk factors remain inconclusive. The purpose of this study was to examine associations between modifiable lifestyle factors and the risk of NPC in the Singaporean population. METHODS: We conducted a case-control study in Singapore with 300 patients and 310 controls who were recruited between 2008 and 2012. Each control was selected and individually matched to each patient based on sex, ethnicity, and age (±5 years). A total of 290 pairs of cases and controls were matched successfully. We examined lifestyle factors such as tobacco smoking, alcohol drinking, various salted and preserved food consumption, and weaning practices. RESULTS: After adjusting for covariates, multivariate analysis showed that those participants who were current smokers and had ever smoked tobacco had a higher risk of NPC than participants who had never smoked, with odds ratios (ORs) of 4.50 (95% confidence interval [CI] 2.58-7.86; P < 0.001) and 2.52 (95% CI 1.54-4.12; P < 0.001), respectively. Those who consumed salted vegetables at least once a week also showed a significantly increased risk of NPC than those who never or rarely consumed salted vegetables, with an OR of 4.18 (95% CI 1.69-10.38; P = 0.002). CONCLUSION: Smoking (currently and ever-smoked) and consuming salted vegetables once a week or more were lifestyle risk factors for NPC, and changes of these factors for the better may reduce the risk of NPC.


Assuntos
Carcinoma/epidemiologia , Neoplasias Nasofaríngeas/epidemiologia , Fumar/efeitos adversos , Cloreto de Sódio na Dieta/efeitos adversos , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Carcinoma/etiologia , Estudos de Casos e Controles , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/etiologia , Razão de Chances , Fatores de Risco , Singapura/epidemiologia , Fumar/epidemiologia
19.
Nat Genet ; 48(12): 1544-1550, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27749845

RESUMO

We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.


Assuntos
Marcadores Genéticos/genética , Predisposição Genética para Doença , Variação Genética/genética , Estudo de Associação Genômica Ampla , Neoplasias Bucais/genética , Infecções por Papillomavirus/genética , Neoplasias Faríngeas/genética , Idoso , Estudos de Casos e Controles , Feminino , Antígenos HLA , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Boca/metabolismo , Boca/patologia , Boca/virologia , Neoplasias Bucais/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Neoplasias Faríngeas/virologia
20.
EBioMedicine ; 10: 117-23, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27377626

RESUMO

Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.


Assuntos
Biomarcadores Tumorais , DNA de Neoplasias , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/genética , Estudos de Casos e Controles , DNA de Neoplasias/sangue , Detecção Precoce de Câncer , Feminino , Humanos , Leucócitos/metabolismo , Neoplasias Pulmonares/sangue , Masculino , Mutação , Estadiamento de Neoplasias , Carcinoma de Pequenas Células do Pulmão/sangue , Proteína Supressora de Tumor p53/genética
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