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1.
Hum Mol Genet ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527138

RESUMO

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained two-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance, and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

2.
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
3.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

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

4.
Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373

RESUMO

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


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
5.
Sci Rep ; 7: 44876, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28332632

RESUMO

Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.


Assuntos
Carcinoma de Células Renais/genética , Deleção Cromossômica , Cromossomos Humanos Y , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases/genética , Neoplasias Renais/genética , Antígenos de Histocompatibilidade Menor/genética , Sobrevivência Celular/genética , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino
6.
Sci Rep ; 6: 31628, 2016 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-27545006

RESUMO

To examine the diversity of somatic alterations and clonal evolution according to aggressiveness of disease, nineteen tumor-blood pairs of 'formerly bronchiolo-alveolar carcinoma (BAC)' which had been reclassified into preinvasive lesion (adenocarcinoma in situ; AIS), focal invasive lesion (minimally invasive adenocarcinoma; MIA), and invasive lesion (lepidic predominant adenocarcinoma; LPA and non-lepidic predominant adenocarcinoma; non-LPA) according to IASLC/ATS/ERS 2011 classification were explored by whole exome sequencing. Several distinct somatic alterations were observed compare to the lung adenocarcinoma study from the Cancer Genome Atlas (TCGA). There were higher numbers of tumors with significant APOBEC mutation fold enrichment (73% vs. 58% TCGA). The frequency of KRAS mutations was lower in our study (5% vs. 32% TCGA), while a higher number of mutations of RNA-splicing genes, RBM10 and U2AF1, were found (37% vs. 11% TCGA). We found neither mutational pattern nor somatic copy number alterations that were specific to AIS/MIA. We demonstrated that clonal cell fraction was the only distinctive feature that discriminated LPA/non-LPA from AIS/MIA. The broad range of clonal frequency signified a more branched clonal evolution at the time of diagnosis. Assessment of tumor clonal cell fraction might provide critical information for individualized therapy as a prognostic factor, however this needs further study.


Assuntos
Desaminases APOBEC/genética , Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica
7.
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
8.
PLoS One ; 10(5): e0125026, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25965386

RESUMO

BACKGROUND: Detection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma that will contribute to early detection of lung cancer. MATERIAL AND METHODS: Plasma samples from 100 early stage (I to IIIA) non-small-cell lung cancer (NSCLC) patients and 100 non-cancer controls were screened for 754 circulating microRNAs via qRT-PCR, using TaqMan MicroRNA Arrays. Logistic regression with a lasso penalty was used to select a panel of microRNAs that discriminate between cases and controls. Internal validation of model discrimination was conducted by calculating the bootstrap optimism-corrected AUC for the selected model. RESULTS: We identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95). This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97) following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone. CONCLUSION: Our 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/sangue , Neoplasias Pulmonares/sangue , MicroRNAs/sangue , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade
9.
Cancer Res ; 74(13): 3525-34, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24760422

RESUMO

Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer.


Assuntos
Neoplasias Pulmonares/complicações , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Infecções por Papillomavirus/etiologia , Adulto , Idoso , Anticorpos Antivirais/imunologia , Inibidor p16 de Quinase Dependente de Ciclina , DNA Viral/análise , DNA Viral/genética , Feminino , Papillomavirus Humano 11/imunologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Papillomavirus Humano 6/imunologia , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/virologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Estudos Prospectivos , RNA Viral/biossíntese , Estudos Retrospectivos
10.
Int J Cancer ; 135(8): 1918-30, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24615328

RESUMO

While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke-lung cancer relationship by histological type based on pooled data from 18 case-control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 control who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack-years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17-1.45) for all histological types combined, 1.26 (95% CI: 1.10-1.44) for adenocarcinoma, 1.41 (95% CI: 0.99-1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89-2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62-5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for nonsmall cell lung cancers (OR=2.11, 95% CI: 1.11-4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Exposição Ambiental , Neoplasias Pulmonares/etiologia , Carcinoma de Pequenas Células do Pulmão/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adenocarcinoma/etiologia , Carcinoma de Células Escamosas/etiologia , Estudos de Casos e Controles , Humanos , Fatores de Risco
11.
Int J Epidemiol ; 38(4): 971-5, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19542184

RESUMO

BACKGROUND: Obesity is a risk factor for several cancers although appears to have an inverse association with cancers strongly related to tobacco. Studying obesity is difficult due to numerous biases and confounding. METHODS: To avoid these biases we used a Mendelian randomization approach incorporating an analysis of variants in the FTO gene that are strongly associated with BMI levels among 7000 subjects from a study of lung, kidney and upper-aerodigestive cancer. RESULTS: The FTO A allele which is linked with increased BMI was associated with a decreased risk of lung cancer (allelic odds ratio (OR) = 0.92, 95% confidence interval (CI) 0.84-1.00). It was also associated with a weak increased risk of kidney cancer, which was more apparent before the age of 50 (OR = 1.44, CI 1.09-1.90). CONCLUSION: Our results highlight the potential for genetic variation to act as an unconfounded marker of environmentally modifiable factors, and offer the potential to obtain estimates of the causal effect of obesity. However, far larger sample sizes than studied here will be required to undertake this with precision.


Assuntos
Neoplasias/etiologia , Obesidade/complicações , Proteínas/genética , Adulto , Idoso , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Europa (Continente)/epidemiologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Variação Genética , Genótipo , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologia , Neoplasias Renais/genética , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias/epidemiologia , Neoplasias/genética , Obesidade/epidemiologia , Obesidade/genética , Fatores de Risco
12.
Nat Genet ; 40(12): 1404-6, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18978790

RESUMO

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.


Assuntos
Cromossomos Humanos Par 5/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Telomerase/genética , Apoptose , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Análise de Componente Principal , Fumar
13.
Clin Cancer Res ; 14(15): 4726-34, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18676741

RESUMO

PURPOSE: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. EXPERIMENTAL DESIGN: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. RESULTS: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. CONCLUSION: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.


Assuntos
Adenocarcinoma de Células Claras/genética , Carcinoma de Células Renais/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Renais/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Adenocarcinoma de Células Claras/metabolismo , Carcinoma de Células Renais/metabolismo , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Mutação , Neoplasias/metabolismo , Regiões Promotoras Genéticas , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
14.
Nature ; 452(7187): 633-7, 2008 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-18385738

RESUMO

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.


Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Subunidades Proteicas/genética , Receptores Nicotínicos/genética , Europa (Continente) , Genótipo , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
15.
Int J Cancer ; 122(8): 1710-5, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18098291

RESUMO

In a multicenter case-control study of renal cell carcinoma (RCC) conducted in central and eastern Europe, we reported a strong inverse association with high vegetable intake and RCC risk. The odds ratio (OR) for high compared to the lowest tertile of vegetable intake was OR = 0.67; (95% confidence interval (CI): 0.53-0.83; p-trend < 0.001). We hypothesized that variation in key folate metabolism genes may modify this association. Common variation in 5 folate metabolism genes (CBS: Ex9+33C > T (rs234706), Ex13 +41C > T (rs1801181), Ex18 -391 G > A (rs12613); MTHFR: A222V Ex5+79C > T (rs1801133), Ex8-62A > C (rs1801131); MTR: Ex26 20A > G (rs1805087), MTRR: Ex5+136 T > C (rs161870), and TYMS:IVS2-405 C > T (rs502396), Ex8+157 C > T (rs699517), Ex8+227 A > G (rs2790)) were analyzed among 1,097 RCC cases and 1,555 controls genotyped in this study. Having at least 1 variant T allele of MTHFR A222V was associated with higher RCC risk compared to those with 2 common (CC) alleles (OR = 1.44; 95% CI: 1.17-1.77; p = 0.001). After stratification by tertile of vegetable intake, the higher risk associated with the variant genotype was only observed in the low and medium tertiles (p-trend = 0.001), but not among those in the highest tertile (p-interaction = 0.22). The association remained robust after calculation of the false discovery rate (FDR = 0.05). Of the 3 TYMS SNPs examined, only the TYMS IVS2 -405 C (rs502396) variant was associated with a significantly lower risk compared to the common genotype (OR = 0.73; 95% CI: 0.57-0.93). Vegetable intake modified the association between all 3 TYMS SNPs and RCC risk (p-interaction < 0.04 for all). In summary, these findings suggest that common variation in MTHFR and TYMS genes may be associated with RCC risk, particularly when vegetable intake is low.


Assuntos
Carcinoma de Células Renais/epidemiologia , Comportamento Alimentar , Ácido Fólico/genética , Neoplasias Renais/epidemiologia , Polimorfismo Genético , Verduras , Adulto , Idoso , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/prevenção & controle , Estudos de Casos e Controles , Europa Oriental/epidemiologia , Feminino , Ácido Fólico/metabolismo , Haplótipos , Humanos , Neoplasias Renais/genética , Neoplasias Renais/prevenção & controle , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Razão de Chances , Medição de Risco , Fatores de Risco , Transdução de Sinais/genética , Timidilato Sintase/genética
16.
Cancer Res ; 67(12): 5667-72, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17575133

RESUMO

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Genes Supressores de Tumor , Neoplasias Pulmonares/genética , Proto-Oncogenes , Proteína Supressora de Tumor p14ARF/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Análise Mutacional de DNA , Feminino , Genes erbB-2 , Genes p53 , Genes ras , Humanos , Imuno-Histoquímica , Masculino , Mutação , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Fumar/efeitos adversos
17.
Hum Mol Genet ; 16(15): 1794-801, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17517688

RESUMO

CHEK2 is a key cell cycle control gene encoding a pluripotent kinase that can cause arrest or apoptosis in response to unrepaired DNA damage. We report a large case-control study of a non-functional variant that had previously been expected to increase cancer rates. Four thousand and fifteen cancer patients (2250 lung, 811 squamous upper aero-digestive and 954 kidney) and 3052 controls in central Europe were genotyped for the mis-sense variant rs17879961 (replacement of T by C), which changes an amino acid (I157T) in an active site of the gene product. The heterozygous (T/C) genotype was associated with a highly significantly lower incidence of lung cancer than the common T/T genotype [relative risk (RR), T/C versus T/T, 0.44, with 95% confidence interval (CI) 0.31-0.63, P < 0.00001] and with a significantly lower incidence of upper aero-digestive cancer (RR 0.44, CI 0.26-0.73, P = 0.001; P = 0.000001 for lung or upper aero-digestive cancer). Protection was significantly greater for squamous than adenomatous lung cancer (P = 0.001). There was an increase of borderline significance in kidney cancer (RR 1.44, CI 0.99-2.00, P = 0.06). This unexpected halving of tobacco-related cancer (since replicated independently) implies much greater absolute risk reduction in smokers than in non-smokers. The mechanism is unknown: perhaps squamous stem cell apoptosis following smoke exposure causes net harm (e.g. by forcing nearby stem cells to divide before they have repaired their own DNA damage from tobacco smoke). If so, reducing the rate of apoptosis by reducing CHEK2 activity could be protective-although not smoking would be far more so.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Fumar/efeitos adversos , Adulto , Idoso , Apoptose , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Risco , Células-Tronco/metabolismo
18.
Cancer Res ; 65(12): 5076-83, 2005 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-15958551

RESUMO

TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.


Assuntos
Genes p53/genética , Genes ras/genética , Neoplasias Pulmonares/genética , Mutação , Fumar/genética , Tirosina/análogos & derivados , Idoso , Ciclo-Oxigenase 2 , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Masculino , Proteínas de Membrana , Pessoa de Meia-Idade , Prostaglandina-Endoperóxido Sintases/biossíntese , Fumar/efeitos adversos , Fumar/metabolismo , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Tirosina/biossíntese
19.
Cancer Epidemiol Biomarkers Prev ; 13(2): 320-3, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14973087

RESUMO

PURPOSE: The objective of the study was to examine the association of three exon 5 variants in the O(6)-alkylguanine DNA alkyltransferase (AGT) gene involved in the repair of the mutagenic DNA lesion O(6)-alkylguanine formed by nitrosamines, with lung cancer risk in never-smokers. EXPERIMENTAL DESIGN: Exon 5 of the AGT gene was sequenced in genomic DNA from 136 cases and 133 hospital- or population-based controls for whom questionnaire information on second-hand smoke and diet was available to determine the frequencies of the Gly(160)Arg, Ile(143)Val, and Lys(178)Arg variant alleles. RESULTS: No codon (160)Arg variant alleles were found in the study population. The codon (143)Val and (178)Arg variant alleles, present at allele frequencies of 0.07, showed 100% linkage. The odds ratio (OR) of lung cancer for these variant carriers was 2.05 [95% confidence interval (CI) 1.03-4.07]. The risk varied between the different lung cancer pathologies with an increased risk for adenocarcinoma (OR 2.67, 95% CI 1.21-5.87) or small cell carcinoma (OR 4.83, 95% CI 0.91-25.7) but not for squamous cell carcinoma (OR 1.07, 95% CI 0.27-4.18). Compared with individuals carrying the mutant alleles unexposed to second-hand smoke, the OR for exposed variant carriers was 1.95 (95% CI 0.53-1.15); a similar interaction, although not significative, was observed for low consumption of cruciferous vegetables and for green vegetables and tomatoes. CONCLUSIONS: These results point toward a role of AGT polymorphisms in lung cancer susceptibility among never-smokers, in particular among subjects exposed to environmental carcinogens.


Assuntos
Adenocarcinoma/etiologia , Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , O(6)-Metilguanina-DNA Metiltransferase/genética , Polimorfismo Genético , Poluição por Fumaça de Tabaco/efeitos adversos , Idoso , Alelos , Estudos de Casos e Controles , Dieta , Éxons , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , O(6)-Metilguanina-DNA Metiltransferase/farmacologia , Reação em Cadeia da Polimerase , Medição de Risco , Análise de Sequência de DNA
20.
Cancer Lett ; 180(1): 33-9, 2002 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-11911967

RESUMO

The level of activity of O6-alkylguanine-DNA-alkyltransferase (AGT), a DNA repair enzyme, in blood lymphocytes may be a marker of susceptibility to lung cancer. We measured the AGT activity level, expressed as pmoles of repaired bases/mg protein, in leukocytes of 153 lung cancer cases (of whom 80 were never smokers) and 106 controls (76 never smokers) enrolled in eight centres from seven countries. Subjects were interviewed with respect to active smoking and exposure to environmental tobacco smoke (ETS). Among never smokers, the odds ratios (ORs) of lung cancer were 1.3 (95% confidence interval 0.5-3.9), 1.5 (0.6-4.1) and 1.4 (0.5-3.8) in quartiles of decreasing AGT activity level, as compared to the upper quartile (P value of test for linear trend 0.6). Corresponding ORs among smokers were 3.4 (0.9-13), 2.0 (0.5-8.3) and 0.4 (0.1-1.6) (P value of test for linear trend 0.4). No interaction was suggested between AGT activity level and either cumulative smoking or exposure to ETS. Reduced AGT activity was not clearly associated with increased lung cancer risk in either smokers or non-smokers. However, the small size of our study argues for a prudent interpretation of our results.


Assuntos
Leucócitos/enzimologia , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/epidemiologia , O(6)-Metilguanina-DNA Metiltransferase/farmacologia , Fumar , Idoso , Carcinógenos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances
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