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1.
Sci Rep ; 10(1): 542, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953506

RESUMO

Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.


Assuntos
Analgésicos Opioides/efeitos adversos , Dor do Câncer/tratamento farmacológico , Náusea/induzido quimicamente , Náusea/genética , Polimorfismo de Nucleotídeo Único , Vômito/induzido quimicamente , Vômito/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos Opioides/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
2.
Sci Rep ; 7(1): 16730, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29196725

RESUMO

Smoking-cessation therapy reduces the risk of smoking-related diseases, but is successful only in a fraction of smokers. There is growing evidence that genetic variations in nicotinic acetylcholine receptor (nAChR) subunits influence the risk of nicotine dependence and the ability to quit smoking. To investigate the role of polymorphisms in nAChR genes on smoking quantity and the outcome of smoking-cessation therapies, we carried out an association study on 337 smokers who underwent pharmacotherapy with varenicline, bupropion, nicotine replacement therapy (NRT) alone, or NRT plus bupropion. Smoking habit and abstention were assessed from the number of cigarettes smoked per day (CPD) and the exhaled CO (eCO), at baseline and up to 12 months. We genotyped seven polymorphisms in genes encoding the nAChR subunits CHRNA4, CHRNA5, and CHRNB2. At baseline, both CPD and eCO were associated with polymorphisms in the CHRNA5 locus (rs503464, rs55853698, rs55781567 and rs16969968; P < 0.01). rs503464, a variant in the 5'-UTR of CHRNA5, was also associated with short-, mid- and long-term responses to therapy (P = 0.011, P = 0.0043, P = 0.020, respectively), although after correction for multiple testing only the association at the mid-term assessment remained significant (FDR = 0.03). These data support the role of individual genetic makeup in the ability to quit smoking.


Assuntos
Proteínas do Tecido Nervoso/genética , Receptores Nicotínicos/genética , Agentes de Cessação do Hábito de Fumar/administração & dosagem , Fumar/terapia , Tabagismo/genética , Regiões 5' não Traduzidas , Adulto , Idoso , Bupropiona/administração & dosagem , Bupropiona/farmacologia , Monóxido de Carbono/análise , Expiração , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Fumar/genética , Dispositivos para o Abandono do Uso de Tabaco , Tabagismo/terapia , Vareniclina/administração & dosagem , Vareniclina/farmacologia , Adulto Jovem
3.
Sci Rep ; 7: 42185, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28181565

RESUMO

Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes.


Assuntos
Adenocarcinoma/genética , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Proteína 2 Reguladora do Ferro/genética , Neoplasias Pulmonares/genética , Complexo de Endopeptidases do Proteassoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
4.
Oncotarget ; 7(19): 27889-98, 2016 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-27058892

RESUMO

Read-through transcripts result from the continuous transcription of adjacent, similarly oriented genes, with the splicing out of the intergenic region. They have been found in several neoplastic and normal tissues, but their pathophysiological significance is unclear. We used high-throughput sequencing of cDNA fragments (RNA-Seq) to identify read-through transcripts in the non-involved lung tissue of 64 surgically treated lung adenocarcinoma patients. A total of 52 distinct read-through species was identified, with 24 patients having at least one read-through event, up to a maximum of 17 such transcripts in one patient. Sanger sequencing validated 28 of these transcripts and identified an additional 15, for a total of 43 distinct read-through events involving 35 gene pairs. Expression levels of 10 validated read-through transcripts were measured by quantitative PCR in pairs of matched non-involved lung tissue and lung adenocarcinoma tissue from 45 patients. Higher expression levels were observed in normal lung tissue than in the tumor counterpart, with median relative quantification ratios between normal and tumor varying from 1.90 to 7.78; the difference was statistically significant (P < 0.001, Wilcoxon's signed-rank test for paired samples) for eight transcripts: ELAVL1-TIMM44, FAM162B-ZUFSP, IFNAR2-IL10RB, INMT-FAM188B, KIAA1841-C2orf74, NFATC3-PLA2G15, SIRPB1-SIRPD, and SHANK3-ACR. This report documents the presence of read-through transcripts in apparently normal lung tissue, with inter-individual differences in patterns and abundance. It also shows their down-regulation in tumors, suggesting that these chimeric transcripts may function as tumor suppressors in lung tissue.


Assuntos
Adenocarcinoma/genética , Neoplasias Pulmonares/genética , Pulmão/patologia , Proteínas Mutantes Quiméricas/genética , Splicing de RNA , Proteínas Supressoras de Tumor/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma de Pulmão , Idoso , DNA Complementar/genética , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Pneumonectomia , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA
5.
Int J Cancer ; 136(5): E262-71, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25196286

RESUMO

In lung cancer, the survival of patients with the same clinical stage varies widely for unknown reasons. In this two-phase study, we examined the hypothesis that germline variations influence the survival of patients with lung adenocarcinoma. First, we analyzed existing genotype and clinical data from 289 UK-resident patients with lung adenocarcinoma, identifying 86 single nucleotide polymorphisms (SNPs) that associated with survival (p < 0.01). We then genotyped these candidate SNPs in a validation series of 748 patients from Italy that resulted genetically compatible with the UK series based on principal component analysis. In a Cox proportional hazard model adjusted for age, sex and clinical stage, four SNPs were confirmed on the basis of their having a hazard ratio (HR) indicating the same direction of effect in the two series and p < 0.05. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, protein tyrosine phosphatase, receptor type, G; the C allele was associated with poorer survival in both patient series (pooled analysis loge HR = 0.31; 95% CI: 0.15-0.46, p = 8.5 × 10(-5) ). PTPRG mRNA levels in 43 samples of lung adenocarcinoma were 40% of those observed in noninvolved lung tissue from the same patients. PTPRG overexpression significantly inhibited the clonogenicity of A549 lung carcinoma cells and the anchorage-independent growth of the NCI-H460 large cell lung cancer line. These four germline variants represent promising candidates that, with further study, may help predict clinical outcome. In addition, the PTPRG locus may have a role in tumor progression.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Seguimentos , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Prognóstico , Taxa de Sobrevida , Estudos de Validação como Assunto , População Branca
6.
PLoS Genet ; 10(4): e1004307, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24743582

RESUMO

Pulmonary adenoma susceptibility 1 (Pas1) is the major locus responsible for lung tumor susceptibility in mice; among the six genes mapping in this locus, Kras is considered the best candidate for Pas1 function although how it determines tumor susceptibility remains unknown. In an (A/J × C57BL/6)F4 intercross population treated with urethane to induce lung tumors, Pas1 not only modulated tumor susceptibility (LOD score = 48, 69% of phenotypic variance explained) but also acted, in lung tumor tissue, as an expression quantitative trait locus (QTL) for Kras-4A, one of two alternatively spliced Kras transcripts, but not Kras-4B. Additionally, Kras-4A showed differential allelic expression in lung tumor tissue of (A/J × C57BL/6)F4 heterozygous mice, with significantly higher expression from the A/J-derived allele; these results suggest that cis-acting elements control Kras-4A expression. In normal lung tissue from untreated mice of the same cross, Kras-4A levels were also highly linked to the Pas1 locus (LOD score = 23.2, 62% of phenotypic variance explained) and preferentially generated from the A/J-derived allele, indicating that Pas1 is an expression QTL in normal lung tissue as well. Overall, the present findings shed new light on the genetic mechanism by which Pas1 modulates the susceptibility to lung tumorigenesis, through the fine control of Kras isoform levels.


Assuntos
Adenoma/genética , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Locos de Características Quantitativas/genética , Alelos , Animais , Mapeamento Cromossômico/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polimorfismo de Nucleotídeo Único/genética
7.
Int J Cancer ; 135(8): 1812-21, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-24599520

RESUMO

The findings of mutations and the development of targeted therapies have improved lung cancer management. Still, the prognosis remains poor, and we need to know more about the genetic and epigenetic alterations in lung cancer. MicroRNAs are involved in crucial biological processes like carcinogenesis by regulating gene expression at the post-transcriptional level. In this project, we have studied the microRNA expression of lung adenocarcinomas and corresponding normal lung tissue and correlated the expression with clinical data and EGFR- and KRAS-mutational status. Agilent microarrays have been used, examining microRNA expression in 154 surgically resected lung adenocarcinomas and 20 corresponding normal lung tissue samples. Findings were confirmed by RT-qPCR in the same cohort and in an independent cohort of 103 lung cancer patients. EGFR and KRAS mutation analyses were also performed. 129 microRNAs were significantly differentially expressed in lung adenocarcinomas compared with normal lung tissue, and 17 microRNAs were differentially expressed between EGFR-mutated and EGFR wildtype tumors. We identified microRNAs associated with time to progression. We have identified several aberrantly expressed microRNAs that discriminate lung adenocarcinomas from normal lung tissue, and hence may be potential biomarkers for early detection. We have found microRNAs that are differentially expressed between EGFR-mutated and EGFR wildtype lung adenocarcinomas, suggesting that microRNAs can be used as molecular biomarkers in classification. We hypothesize that microRNA expression can be used as biomarkers for clinical course.


Assuntos
Adenocarcinoma/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/metabolismo , MicroRNAs/genética , Transcriptoma , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma de Pulmão , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
8.
PLoS One ; 9(2): e88302, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24505471

RESUMO

AIRmax (maximal inflammation) and AIRmin (minimal inflammation) mice show distinct susceptibilities to pristane-induced arthritis (PIA). The Slc11a1 gene, which regulates macrophage and neutrophil activity, is involved in this infirmity. AIRmax (SS) mice homozygous for the non-functional Slc11a1 S (gly169asp) allele obtained by genotype-assisted crosses from AIRmax and AIRmin mice are more susceptible than mice homozygous for the Slc11a1 resistant (R) allele. The present work sought to identify the quantitative trait loci (QTL) regulating PIA and to examine the interactions of these QTL with Slc11a1 alleles in modulating PIA. Mice were given two ip injections of 0.5 mL pristane at 60 day intervals, and the incidence and severity of PIA was scored up to 160 days. Genome-wide linkage studies were performed to search for arthritis QTL in an F2 (AIRmax × AIRmin, n = 290) population. Significant arthritis QTL (LODscore>4) were detected on chromosomes 5 and 8, and suggestive QTL on chromosomes 7, 17 and 19. Global gene expression analyses performed on Affymetrix mouse 1.0 ST bioarrays (27k genes) using RNA from arthritic or control mice paws showed 419 differentially expressed genes between AIRmax and AIRmin mice and demonstrated significantly (P<0.001) over-represented genes related to inflammatory responses and chemotaxis. Up-regulation of the chemokine genes Cxcl1, Cxcl9, Cxcl5, Cxcl13 on chromosome 5 was higher in AIRmax(SS) than in the other lines. Macrophage scavenger receptor 1 and hemeoxigenase (decycling) 1 genes on chromosome 8 were also expressed at higher levels in AIRmax(SS) mice. Our results show that the gene expression profiles of the two arthritis QTL (on chromosomes 5 and 8) correlate with Slc11a1 alleles, resulting in enhanced AIRmax(SS) mice susceptibility to PIA.


Assuntos
Artrite/genética , Proteínas de Transporte de Cátions/genética , Locos de Características Quantitativas , Alelos , Animais , Artrite/induzido quimicamente , Suscetibilidade a Doenças , Feminino , Inflamação/induzido quimicamente , Inflamação/genética , Masculino , Camundongos , Terpenos , Transcriptoma
9.
BMC Genomics ; 14: 724, 2013 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-24148528

RESUMO

BACKGROUND: The genetic basis of susceptibility to renal tumorigenesis has not yet been established in mouse strains. Mouse lines derived by bidirectional phenotypic selection on the basis of their maximal (AIRmax) or minimal (AIRmin) acute inflammatory responsiveness differ widely in susceptibility to spontaneous and urethane-induced renal tumorigenesis. To map the functional loci modulating renal tumor susceptibility in these mice, we carried out a genome-wide genetic linkage study, using SNP arrays, in an (AIRmax x AIRmin)F2 intercross population treated with a single urethane dose at 1 week of age and phenotyped for renal tumors at 35 weeks of age. RESULTS: AIRmax mice did not develop renal tumors spontaneously nor in response to urethane, whereas in AIRmin mice renal tumors formed spontaneously (in 52% of animals) and after urethane induction (89%). The tumors had a papillary morphology and were positive for alpha-methylacyl-CoA racemase and negative for CD10. By analysis of 879 informative SNPs in 662 mice, we mapped a single quantitative trait locus modulating the incidence of renal tumors in the (AIRmax x AIRmin)F2 intercross population. This locus, which we named Renal tumor modifier QTL 1 (Rtm1), mapped to chromosome 17 at 23.4 Mb (LOD score = 15.8), with SNPs rs3696835 and rs3719497 flanking the LOD score peak. The A allele of rs3719497 from AIRmin mice was associated with a 2.5-fold increased odds ratio for renal tumor development. The LOD score peak included the Tuberous sclerosis 2 (Tsc2) gene which has already been implicated in kidney disease: loss of function by germline retroviral insertion is associated with spontaneous renal tumorigenesis in the Eker rat, and heterozygous-null Tsc2(+/-) mice develop renal cystadenomas. CONCLUSIONS: We mapped Rtm1 as a single major locus modulating renal tumorigenesis in a murine intercross population. Thus, the AIR mouse lines can be considered a new genetic model for studying the role of germline and somatic molecular alterations in kidney neoplastic disease.


Assuntos
Genoma , Neoplasias Renais/genética , Animais , Cruzamentos Genéticos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Ligação Genética , Genótipo , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Escore Lod , Camundongos , Neprilisina/genética , Neprilisina/metabolismo , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo
10.
Carcinogenesis ; 34(12): 2767-73, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23978379

RESUMO

Lung adenocarcinoma patients of similar clinical stage and undergoing the same treatments often have marked interindividual variations in prognosis. These clinical discrepancies may be due to the genetic background modulating an individual's predisposition to fighting cancer. Herein, we hypothesized that the lung microenvironment, as reflected by its expression profile, may affect lung adenocarcinoma patients' survival. The transcriptome of non-involved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, was evaluated using whole-genome expression microarrays (with probes corresponding to 28 688 well-annotated coding sequences). Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and retested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Ten genes for which the loge-transformed hazard ratios expressed the same direction of effect in the discovery (P < 1.0 × 10(-3)) and validation series comprised the gene expression signature associated with survival: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10 and SERPINH1. RNA sequencing highlighted the complex expression pattern of these genes in non-involved lung tissue from different patients and permitted the detection of a read-through gene fusion between PPP3R1 and the flanking gene (CNRIP1) as well as a novel isoform of CNTNAP1. Our findings support the hypothesis that individual genetic characteristics, evidenced by the expression pattern of non-involved tissue, influence the outcome of lung adenocarcinoma patients.


Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Transcriptoma/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/genética
11.
BMC Cancer ; 12: 512, 2012 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-23140419

RESUMO

BACKGROUND: Risk factors for lung cancer, such as cigarette smoking, environmental pollution, asbestos, and genetic determinants, are well-known, whereas involvement of the human papillomavirus (HPV) is still unclear. METHODS: We examined a series of 100 lung cancer patients from Italy and the UK for the presence of HPV DNA in both lung tumor specimens and adjacent non-tumoral specimens from the same patients. Thirty-five of the most clinically relevant HPV types were assayed using PCR amplification of the highly conserved L1 region of the viral genome followed by hybridization with specific probes. RESULTS: No HPV was detected in tumor specimens nor in normal lung tissue of any patient. CONCLUSIONS: These data indicate that, in this Western series, HPV is not associated with the risk of lung cancer. Our findings will help refine estimates of lung cancer risk in patients affected by a common viral infection involved in other types of human cancer.


Assuntos
Carcinoma/virologia , DNA Viral/análise , Neoplasias Pulmonares/virologia , Infecções por Papillomavirus/epidemiologia , Idoso , Carcinoma/patologia , Feminino , Humanos , Pulmão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Reação em Cadeia da Polimerase
12.
G3 (Bethesda) ; 2(9): 1041-6, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22973541

RESUMO

Alleles derived from skin tumor-resistant Car-R mice provide resistance to both skin and lung tumorigenesis over the susceptibility of the SWR/J strain. In an effort to map tumor modifier loci affecting both tumor types, we carried out a genetic linkage analysis in backcross SWR/J x (SWR/J x Car-R) mice and identified a locus (Lsktm1) on chromosome 1 linked to both skin (LOD score = 3.93) and lung (LOD score = 8.74) tumorigenesis. Two genes, Igfbp5 and Igfbp2, residing in this locus and belonging to the insulin-like growth factor binding protein family were expressed at significantly greater levels in normal lung tissue from cancer-resistant Car-R mice than in cancer-susceptible SWR/J mice. Overexpression of the recombinant Igfbp5 and Igfbp2 genes in two lung cancer cell lines significantly inhibited clonogenicity (P < 0.0001). Collectively, we have identified a single polymorphic locus that affects skin and lung tumorigenesis and identify Igfbp5 and Igfbp2 as candidate modifier genes of lung tumorigenesis.


Assuntos
Transformação Celular Neoplásica/genética , Loci Gênicos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 5 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Neoplasias Pulmonares/genética , Neoplasias Cutâneas/genética , Animais , Linhagem Celular Tumoral , Mapeamento Cromossômico , Cromossomos de Mamíferos , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Polimorfismo de Nucleotídeo Único , Receptores de Trombina/genética , Ensaio Tumoral de Célula-Tronco
13.
Int J Cancer ; 131(5): E643-8, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22223368

RESUMO

Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in noninvolved lung tissue might correlate with clinical stage in lung adenocarcinoma (ADCA) patients, we compared the transcriptome of noninvolved lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with stage>I. Quantitative PCR of 10 genes with the most significant differential expression confirmed the statistical association with clinical stage in eight genes, six of which were downregulated in high-stage patients. Five of these six genes were also downregulated in lung ADCA tissue as compared to noninvolved tissue. Studies in vitro indicated that four of the genes (SLC14A1, SMAD6, TMEM100 and TXNIP) inhibited colony formation of lung cancer cell lines transfected to overexpress the genes, suggesting their potential tumor-suppressor activity. Our findings suggest that individual variations in the transcriptional profile of noninvolved lung tissue may reflect the lung ADCA patient's predisposition to tumor aggressiveness.


Assuntos
Adenocarcinoma/genética , Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Pulmão/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-Tronco
14.
Mol Cancer ; 10: 81, 2011 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-21736709

RESUMO

BACKGROUND: The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1-EcoRI polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations. RESULTS: Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site. CONCLUSION: SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.


Assuntos
Regiões 5' não Traduzidas/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas/fisiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes Supressores de Tumor , Predisposição Genética para Doença , Células HEK293 , Células HT29 , Células Hep G2 , Humanos , Desequilíbrio de Ligação , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Polimorfismo de Nucleotídeo Único/fisiologia , Regiões Promotoras Genéticas/fisiologia , Simportadores , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/fisiologia
15.
Clin Cancer Res ; 17(13): 4581-7, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21622719

RESUMO

PURPOSE: Patients treated with opioid drugs for cancer pain experience different relief responses, raising the possibility that genetic factors play a role in opioid therapy outcome. In this study, we tested the hypothesis that genetic variations may control individual response to opioid drugs in cancer patients. EXPERIMENTAL DESIGN: We tested 1 million single-nucleotide polymorphisms (SNP) in European cancer patients, selected in a first series, for extremely poor (pain relief ≤40%; n = 145) or good (pain relief ≥90%; n = 293) responses to opioid therapy using a DNA-pooling approach. Candidate SNPs identified by SNP-array were genotyped in individual samples constituting DNA pools as well as in a second series of 570 patients. RESULTS: Association analysis in 1,008 cancer patients identified eight SNPs significantly associated with pain relief at a statistical threshold of P < 1.0 × 10⁻³, with rs12948783, upstream of the RHBDF2 gene, showing the best statistical association (P = 8.1 × 10⁻9). Functional annotation analysis of SNP-tagged genes suggested the involvement of genes acting on processes of the neurologic system. CONCLUSION: Our results indicate that the identified SNP panel can modulate the response of cancer patients to opioid therapy and may provide a new tool for personalized therapy of cancer pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Loci Gênicos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Dor/tratamento farmacológico , Dor/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Dor/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Serina Endopeptidases , Serina Proteases/genética , Resultado do Tratamento
16.
Clin Cancer Res ; 17(8): 2410-6, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21242121

RESUMO

PURPOSE: The main prognostic factor of lung cancer patient outcome is clinical stage, a parameter of tumor aggressiveness. Our study was conducted to test whether germ line variations modulate individual differences in clinical stage. EXPERIMENTAL DESIGN: We conducted a case-only genome-wide association study (GWAS) using a 620,901 single-nucleotide polymorphism (SNP) array in a first series of 600 lung adenocarcinoma (ADCA) patients and in a replication series of 317 lung ADCA patients. RESULTS: GWAS identified 54 putatively associated SNPs, 3 of which were confirmed in the replication series. Joint analysis of the two series pointed to 22 statistically associated (P < 0.01) genetic variants that together explained about 20% of the phenotypic variation in clinical staging (P < 2 × 10(-16)) and showed a statistically significant difference in overall survival (P = 8.0 × 10(-8)). The strongest statistical association was observed at rs10278557 (P = 1.1 × 10(-5)), located in the mesenchyme homeobox 2 (MEOX2) gene. CONCLUSION: These data point to the role of germ line variations involving multiple loci in modulating clinical stage and, therefore, prognosis in lung ADCA patients.


Assuntos
Adenocarcinoma/genética , Estudo de Associação Genômica Ampla/métodos , Neoplasias Pulmonares/genética , Estadiamento de Neoplasias/métodos , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Loci Gênicos/genética , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias/estatística & dados numéricos , Polimorfismo de Nucleotídeo Único , Modelos de Riscos Proporcionais , Adulto Jovem
17.
J Natl Cancer Inst ; 102(17): 1366-70, 2010 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-20733116

RESUMO

Chromosomal locus 15q25, implicated in lung cancer risk and nicotine dependence, shows extensive linkage disequilibrium that complicates identification of causal variation. Cholinergic receptor nicotinic alpha5 (CHRNA5) has been identified as a lung cancer risk factor. We identified by sequence analysis three haplotypes (delTTC, insATC, and insTGG) in the 5' promoter region and three at the 3'-untranslated region of CHRNA5. Linkage disequilibrium analysis of the 5' variants showed that the insTGG haplotype is associated with three tightly linked risk alleles (nicotine dependence, lung cancer, and chronic obstructive pulmonary disease). The three CHRNA5 promoter haplotypes were statistically significantly associated with lung CHRNA5 transcript levels, determined by real-time polymerase chain reaction. In nontumor lung parenchyma from 68 patients who underwent lung lobectomy, the delTTC haplotype was associated with the highest CHRNA5 transcript levels (relative quantification units = 1.82), whereas the insTGG haplotype was associated with the lowest (0.88 units, P(diff) < .001, Welch t test; all statistical tests were two-sided). Luciferase reporter assays in human lung cancer cell lines A549, H460, H520, and H596 also showed that the 5' region haplotypes were statistically significantly associated with changes in CHRNA5 promoter activity, whereas the 3'-untranslated region variants were not.


Assuntos
Cromossomos Humanos Par 15 , Desequilíbrio de Ligação , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Receptores Nicotínicos/genética , Transcrição Gênica , Haplótipos , Humanos , Pulmão/metabolismo , Fatores de Risco
18.
J Immunol ; 185(3): 1616-21, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20610646

RESUMO

Genome-wide linkage analysis using single nucleotide polymorphism arrays was carried out in pedigrees of mice differing in the extent of acute inflammatory response (AIRmax or AIRmin). The AIR phenotype was determined by quantifying the number of infiltrating cells in the 24-h exudate induced by Biogel P-100 s.c. injection and by ex vivo IL-1beta production by leukocytes stimulated with LPS and ATP. We mapped the major inflammatory response modulator 1 locus on chromosome 7, at the 1-logarithm of odds (LOD) confidence interval from 116.75 to 139.75 Mb, linked to the number of infiltrating cells (LOD = 3.61) through the production of IL-1beta (LOD = 9.35). Of several interesting candidate genes mapping to the inflammatory response modulator 1 locus, 28 of these were differentially expressed in the bone marrow of AIRmax and AIRmin mice. These findings represent a step toward the identification of the genes underlying this complex phenotype.


Assuntos
Loci Gênicos/imunologia , Mediadores da Inflamação/fisiologia , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Doença Aguda , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Mapeamento Cromossômico , Cruzamentos Genéticos , Feminino , Regulação da Expressão Gênica/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/fisiologia , Escore Lod , Masculino , Camundongos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/imunologia
19.
Cancer Lett ; 295(1): 54-8, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20307927

RESUMO

Non-inbred AIR (AIRmax, AIRmin) and Car (Car-S, Car-R) mouse lines were generated from the same eight inbred mice through bidirectional selective breeding for acute inflammatory response and for susceptibility to two-stage skin tumorigenesis, respectively. Because AIR lines also showed a differential predisposition to skin tumorigenesis and Car lines differed in the extent of inflammatory response, we carried out genome-wide association studies using SNP arrays to identify the genetic elements affecting skin tumor susceptibility and inflammatory response in AIR and Car lines. We found that the phenotypic outcome reflects a specific genetic profile in each mouse line, suggesting that distinct genetic elements, selected by differential genetic drifts, and exerting pleiotropic effects in each mouse population, control the skin tumor susceptibility and inflammatory response phenotypes. These findings point to the complex link between skin tumor susceptibility and inflammatory response in mice.


Assuntos
Heterogeneidade Genética , Predisposição Genética para Doença , Inflamação/genética , Papiloma/genética , Neoplasias Cutâneas/genética , 9,10-Dimetil-1,2-benzantraceno , Animais , Carcinógenos , Deriva Genética , Estudo de Associação Genômica Ampla , Inflamação/patologia , Camundongos , Infiltração de Neutrófilos , Papiloma/induzido quimicamente , Papiloma/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/patologia , Acetato de Tetradecanoilforbol
20.
Cancer Lett ; 294(2): 187-94, 2010 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-20189714

RESUMO

AIRmax and AIRmin mouse lines show a differential lung inflammatory response and differential lung tumor susceptibility after urethane treatment. The transcript profile of approximately 24,000 known genes was analyzed in normal lung tissue of untreated and urethane-treated AIRmax and AIRmin mice. In lungs of untreated mice, inflammation-associated genes involved in pathways such as "leukocyte transendothelial migration", "cell adhesion" and "tight junctions" were differentially expressed. Moreover, gene expression levels differed significantly in urethane-treated mice; in AIRmin mice, modulation of expression of genes involved in pathways associated with inflammatory response paralleled the previously observed persistent infiltration of inflammatory cells in the lung of these mice.


Assuntos
Transformação Celular Neoplásica/genética , Neoplasias Pulmonares/genética , Pulmão/fisiologia , Pneumonia/genética , Animais , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Feminino , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Pneumonia/induzido quimicamente , Pneumonia/patologia , Uretana
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