RESUMEN
The associations between variants of human papillomavirus (HPV) 16 and risk of cervical neoplasia have been reported, but nucleotide variations of HPV 16 in Asian populations and their association with cervical neoplasia have not been evaluated extensively. During 1991-1992, 11,923 women from seven townships in Taiwan were enrolled. The HPV DNA in cervical cells was detected and genotyped using EasyChip HPV blot. Nucleotide variations in the long control region (LCR), E6, and E7 genes were determined using DNA sequencing for 170 HPV 16-positive cervical samples. The Asian variant was the most prevalent variant (81.8%) of HPV 16 in Taiwan, and was also associated with increased prevalence of histologically confirmed cervical intraepithelial neoplasia grade 3 or worse, showing an age-adjusted odds ratio (exact confidence limits) of 10.70 (1.62-451.05; P = 0.0049) compared to the HPV 16 European variant. Similar significant associations with cervical intraepithelial neoplasia grade 3 or worse were also observed for distinct nucleotide substitutions, including T178A/G, A647G, A7730C/G, T7781C, G7842A, and C24T/G. These results demonstrate that non-European variants (non-E) of HPV 16, predominantly Asian variants, are associated with increased risk for severe cervical neoplasia, compared with European variants. Molecular mechanisms accounting for varied cervical neoplasia risk among different HPV 16 variants warrant further investigation.
Asunto(s)
Variación Genética , Papillomavirus Humano 16/clasificación , Papillomavirus Humano 16/genética , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , ADN Viral/química , ADN Viral/genética , ADN Viral/aislamiento & purificación , Femenino , Genotipo , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Persona de Mediana Edad , Epidemiología Molecular , Datos de Secuencia Molecular , Proteínas Oncogénicas Virales/genética , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/epidemiología , Mutación Puntual , Proteínas Represoras/genética , Medición de Riesgo , Análisis de Secuencia de ADN , Taiwán/epidemiología , Neoplasias del Cuello Uterino/epidemiologíaRESUMEN
BACKGROUND: A case-control study was conducted to evaluate the role of adult diet on nasopharyngeal carcinoma (NPC) in Taiwan. METHODS: A total of 375 incident NPC cases and 327 controls matched to the cases on sex, age, and residence were recruited between July 1991 and December 1994. A structured questionnaire inquiring complete dietary history, socio-demographic characteristics, and other potential confounding factors was used in the personal interview. Unconditional logistic regression analysis was used to estimate multivariate-adjusted odds ratio (OR(adj)) with 95% confidence interval (CI) after accounting for known risk factors. RESULTS: Fresh fish (OR(adj), 0.56; 95% CI, 0.38-0.83 for the highest vs. lowest tertile of intake), green tea (OR(adj), 0.61; 95% CI, 0.40-0.91 for drinking ≥1 times/week vs. never) and coffee (OR(adj), 0.56; 95% CI, 0.37-0.85 for drinking ≥0.5 times/week vs. never) were inversely associated with the NPC risk. No association with NPC risk was observed for the intake of meats, salted fish, fresh vegetables, fruits and milk. Intake of vitamin A from plant sources was associated with a decreased NPC risk (OR(adj), 0.62; 95% CI, 0.41-0.94 for the highest vs. lowest tertile). CONCLUSION: The study findings suggest that certain adult dietary patterns might protect against the development of NPC.
Asunto(s)
Café , Ingestión de Líquidos , Peces , Neoplasias Nasofaríngeas/epidemiología , Plantas/química , Té , Vitaminas , Adulto , Anciano , Animales , Carcinoma , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/prevención & control , Factores de Riesgo , Taiwán/epidemiologíaRESUMEN
BACKGROUND: The association between human leukocyte antigen (HLA) genes (located in the Major Histocompatibility Complex [MHC] region of chromosome 6p21) and NPC has been known for some time. Recently, two genome-wide association studies (GWAS) conducted in Taiwan and China confirmed that the strongest evidence for NPC association was mapped to the MHC region. It is still unclear, however, whether these findings reflect direct associations with Human Leukocyte Antigen (HLA) genes and/or to other genes in this gene-rich region. METHODS: To better understand genetic associations for NPC within the MHC region of chromosome 6, we conducted an evaluation that pooled two previously conducted NPC case-control studies in Taiwan (N = 591 cases and N = 521 controls). PCR-based genotyping was performed for 12 significant SNPs identified within 6p21 in the Taiwan NPC GWAS and for the HLA-A gene (exons 2 and 3). FINDINGS: After confirming homogeneity between the two studies, pooled odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. We found that HLA-A (p-trend = 0.0006) and rs29232 (within the GABBR1 gene; p-trend = 0.005) were independent risk factors for NPC after adjustment for age, gender, study and each other. NPC risk was highest among individuals who were homozygous for the HLA-A*0207 risk allele and carriers of the rs29232 risk allele (A). CONCLUSION: Our study suggests that most of the SNPs significantly associated with NPC from GWAS reflect previously identified HLA-A associations. An independent effect of rs29232 (GABBR1), however, remained, suggesting that additional genes within this region might be associated with NPC risk.
Asunto(s)
Cromosomas Humanos Par 6/genética , Predisposición Genética a la Enfermedad , Antígenos HLA-A/genética , Neoplasias Nasofaríngeas/genética , Alelos , Carcinoma , Intervalos de Confianza , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Haplotipos/genética , Humanos , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Oportunidad Relativa , Factores de Riesgo , TaiwánRESUMEN
PURPOSE: Epstein-Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families. EXPERIMENTAL DESIGN: We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated. RESULTS: A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4-16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5-61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker. CONCLUSIONS: Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity.
Asunto(s)
Anticuerpos Antivirales/sangre , Antígenos Virales/inmunología , Carcinoma/diagnóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/inmunología , Inmunoglobulina A/sangre , Neoplasias Nasofaríngeas/diagnóstico , Adulto , Anciano , Antígenos Virales/sangre , Proteínas de la Cápside/inmunología , Carcinoma/etiología , Carcinoma/virología , Desoxirribonucleasas/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/etiología , Neoplasias Nasofaríngeas/virología , Oportunidad Relativa , Pronóstico , Curva ROC , Factores de RiesgoRESUMEN
In the present study, the authors compared the long-term risk of nasopharyngeal carcinoma (NPC) of male participants in an NPC multiplex family cohort with that of controls in a community cohort in Taiwan after adjustment for anti-Epstein-Barr virus (EBV) seromarkers and cigarette smoking. A total of 43 incident NPC cases were identified from the 1,019 males in the NPC multiplex family cohort and the 9,622 males in the community cohort, for a total of 8,061 person-years and 185,587 person-years, respectively. The adjusted hazard ratio was 6.8 (95% confidence interval (CI): 2.3, 20.1) for the multiplex family cohort compared with the community cohort. In the evaluation of anti-EBV viral capsid antigen immunoglobulin A and anti-EBV deoxyribonuclease, the adjusted hazard ratios were 2.8 (95% CI: 1.3, 6.0) and 15.1 (95% CI: 4.2, 54.1) for those positive for 1 EBV seromarker and positive for both seromarkers, respectively, compared with those negative for both EBV seromarkers. The adjusted hazard ratio was 31.0 (95% CI: 9.7, 98.7) for participants who reported a family history of NPC and who were anti-EBV-seropositive compared with individuals without such a history who were anti-EBV-seronegative. The findings suggest that both family history of NPC and anti-EBV seropositivity are important determinants of subsequent NPC risk and that the effect of family history on NPC risk cannot be fully explained by mediation through EBV serologic responses.
Asunto(s)
Predisposición Genética a la Enfermedad/epidemiología , Herpesvirus Humano 4/inmunología , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/etiología , Adulto , Antígenos Virales/sangre , Biomarcadores de Tumor/sangre , Estudios de Cohortes , Desoxirribonucleasas/sangre , Familia , Femenino , Humanos , Inmunoglobulina A/sangre , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/sangre , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sistema de Registros , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiología , Encuestas y Cuestionarios , Taiwán/epidemiología , Proteínas Virales/sangreRESUMEN
Human papillomavirus (HPV) 52 and 58 are oncogenic HPV types prevalent in Asia. Our study aims to explore intratypic variants of HPV 52 and 58 in Taiwan. A total of 11,923 women were enrolled from seven townships in 1991-1992. HPV DNA in their cervical cells was detected and typed by EasyChip® HPV blot. Among 424 participants infected with HPV 52 and/or 58, nucleotide variations were determined in cervical cell samples of 406 participants by the polymerase chain reaction sequencing of the long control region, E6 and E7 genes. Nonprototype-like variants including lineages B and C were detected in 278 (99.3%) of 280 HPV 52 samples. The prototype and prototype-like group (lineage A) of HPV58 was found in 132 (98.5%) of 134 HPV 58 samples, with sublineage A1, A2 and A3 variant in 14.2, 27.6 and 56.7%, respectively. Among women infected with single HPV 52 type, the C variant (vs. B variant) was associated with an increased prevalence of cytologically diagnosed high-grade squamous intraepithelial lesion or worse lesions showing an age-adjusted odds ratio (95% confidence interval, CI) of 5.2 (1.0-27.6) and an increased prevalence of histologically confirmed high-grade cervical intraepithelial neoplasia or more severe lesions with an age-adjusted odds ratio (95% CI) of 7.6 (1.3-43.8). It was concluded that frequency distributions of HPV 52 and 58 variants in Taiwan were different from those in European and American populations. The association between C variant of HPV 52 and prevalence of cervical neoplasia needs further validation.
Asunto(s)
Carcinoma de Células Escamosas/etiología , ADN Viral/genética , Variación Genética , Papillomaviridae/genética , Infecciones por Papillomavirus/complicaciones , Displasia del Cuello del Útero/etiología , Neoplasias del Cuello Uterino/etiología , Adulto , Anciano , Secuencia de Bases , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Estadificación de Neoplasias , Papillomaviridae/clasificación , Papillomaviridae/patogenicidad , Proteínas E7 de Papillomavirus/genética , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Filogenia , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Ácido Nucleico , Taiwán , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Frotis Vaginal , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virologíaRESUMEN
Genetic and environmental factors have been implicated in the etiology of nasopharyngeal carcinoma (NPC), a tumor known to be closely associated with Epstein-Barr virus (EBV) infection. Studies have reported familial aggregation of NPC and have suggested the possible aggregation of NPC and other cancers. We evaluated familial aggregation of cancer in 358 high-risk families with two or more NPC cases enrolled in a NPC genetics study in Taiwan. Participants were linked to the Taiwan National Cancer Registry to identify incident cancers diagnosed after study enrollment (started in 1996) and before December 31, 2005, or death. In total, 2,870 individuals from the NPC Multiplex Family Study contributed 15,151 person-years over an average of 5.3 years of follow-up. One hundred ten incident cancers were identified. Multiple-primary standardized incidence ratios (MP-SIRs) were computed to evaluate overall cancer risk associated with infectious agents and with other tumors. The overall MP-SIR was 1.3 (95% CI: 1.1-1.6), which was largely explained by an excess in NPC (MP-SIR = 15; 95% CI: 10-23). Exclusion of incident NPC diagnoses led to an overall MP-SIR of 1.0 (95% CI: 0.83-1.3). Similarly, the observed excess risk of cancers associated with infectious agents (MP-SIR = 2.0; 95% CI: 1.5-2.6) was driven by the excess in NPC; exclusion of NPC cases led to a reduced MP-SIR that did not differ from 1.0. Analysis of the largest NPC multiplex family study to date confirms the presence of coaggregation of NPC within families in Taiwan but does not provide evidence for a broader familial syndrome involving NPC and other tumors.
Asunto(s)
Carcinoma/epidemiología , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Primarias Múltiples/epidemiología , Carcinoma/genética , Carcinoma/virología , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Femenino , Humanos , Masculino , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virología , Neoplasias Primarias Múltiples/microbiología , Linaje , Sistema de Registros , Factores de Riesgo , TaiwánRESUMEN
Using highly sensitive microarray-based procedures, we identified eight microRNAs (miRNAs) showing robust differential expression between 31 laser-capture-microdissected nasopharyngeal carcinomas (NPCs) and 10 normal healthy nasopharyngeal epithelial samples. In particular, miRNA mir-29c was expressed at one-fifth the levels in tumors as in normal epithelium. In NPC tumors, the lower mir-29c levels correlated with higher levels of multiple mRNAs whose 3' UTRs can bind mir-29c at target sequences conserved across many vertebrates. In cultured cells, introduction of mir-29c down-regulated these genes at the level of mRNA and inhibited expression of luciferase encoded by vectors having the 3' UTRs of these genes. Moreover, for each of several genes tested, mutating the mir-29c target sites in the 3' UTR abrogated mir-29c-induced inhibition of luciferase expression. Most of the mir-29c-targeted genes identified encode extracellular matrix proteins, including multiple collagens and laminin gamma1, that are associated with tumor cell invasiveness and metastatic potential, prominent characteristics of NPC. Thus, we identify eight miRNAs differentially expressed in NPC and demonstrate the involvement of one in regulating genes involved in metastasis.
Asunto(s)
Proteínas de la Matriz Extracelular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Neoplasias Nasofaríngeas/genética , Estudios de Casos y Controles , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , MicroARNs/fisiología , ARN Mensajero , Regulación hacia ArribaRESUMEN
Polymorphisms in nitrosamine metabolism, DNA repair, and immune response genes have been associated with nasopharyngeal carcinoma (NPC). Studies have suggested chromosomal regions involved in NPC. To shed light on NPC etiology, we evaluated host gene expression patterns in 31 NPC and 10 normal nasopharyngeal tissue specimens using the Affymetrix Human Genome U133 Plus 2.0 Array. We focused on genes in five a priori biological pathways and chromosomal locations. Rates of differential expression within these prespecified lists and overall were tested using a bootstrap method. Differential expression was observed for 7.6% of probe sets overall. Elevations in rate of differential expression were observed within the DNA repair (13.7%; P = 0.01) and nitrosamine metabolism (17.5%; P = 0.04) pathways. Differentially expressed probe sets within the DNA repair pathway were consistently overexpressed (93%), with strong effects observed for PRKDC, PCNA, and CHEK1. Differentially expressed probe sets within the nitrosamine metabolism pathway were consistently underexpressed (100%), with strong effects observed for NQ01, CYP2B6, and CYP2E1. No significant evidence of increases in rate of differential expression was seen within the immune/inflammatory pathway. A significant elevation in rate of differential expression was noted for chromosome 4p15.1-4q12 (13.0%; P = 0.04); both overexpression and underexpression were evident (38% and 62%, respectively). An elevation in the rate of differential expression on chromosome 14q32 was observed (11.3%; P = 0.06) with a consistent pattern of gene underexpression (100%; P < 0.0001). These effects were similar when excluding late-stage tumors. Our results suggest that nitrosamine activation and DNA repair are important in NPC. The consistent down-regulation of expression on chromosome 14q32 suggests loss of heterozygosity in this region.
Asunto(s)
Mapeo Cromosómico/métodos , Cromosomas Humanos Par 14/ultraestructura , Reparación del ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias Nasofaríngeas/diagnóstico , Neoplasias Nasofaríngeas/genética , Nitrosaminas/metabolismo , Biopsia , Estudios de Casos y Controles , Regulación de la Expresión Génica , Humanos , Rayos Láser , Pérdida de Heterocigocidad , Modelos Estadísticos , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo Genético , ARN/metabolismoRESUMEN
To identify the molecular mechanisms by which EBV-associated epithelial cancers are maintained, we measured the expression of essentially all human genes and all latent EBV genes in a collection of 31 laser-captured, microdissected nasopharyngeal carcinoma (NPC) tissue samples and 10 normal nasopharyngeal tissues. Global gene expression profiles clearly distinguished tumors from normal healthy epithelium. Expression levels of six viral genes (EBNA1, EBNA2, EBNA3A, EBNA3B, LMP1, and LMP2A) were correlated among themselves and strongly inversely correlated with the expression of a large subset of host genes. Among the human genes whose inhibition was most strongly correlated with increased EBV gene expression were multiple MHC class I HLA genes involved in regulating immune response via antigen presentation. The association between EBV gene expression and inhibition of MHC class I HLA expression implies that antigen display is either directly inhibited by EBV, facilitating immune evasion by tumor cells, and/or that tumor cells with inhibited presentation are selected for their ability to sustain higher levels of EBV to take maximum advantage of EBV oncogene-mediated tumor-promoting actions. Our data clearly reflect such tumor promotion, showing that deregulation of key proteins involved in apoptosis (BCL2-related protein A1 and Fas apoptotic inhibitory molecule), cell cycle checkpoints (AKIP, SCYL1, and NIN), and metastasis (matrix metalloproteinase 1) is closely correlated with the levels of EBV gene expression in NPC.
Asunto(s)
Perfilación de la Expresión Génica , Genoma Humano , Herpesvirus Humano 4/aislamiento & purificación , Antígenos de Histocompatibilidad Clase I/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virología , Biopsia , Genes Virales , Herpesvirus Humano 4/genética , Humanos , Incidencia , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Valores de Referencia , Estados Unidos/epidemiologíaRESUMEN
The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests that it might also serve as a screening test for individuals who are at high risk for developing NPC. We previously demonstrated that unaffected individuals from high-risk families had elevated anti-EBV antibody levels compared to community controls. In this study, we measured EBV load using 2 different real-time PCR assays (targeting BamH1W and polymerase gene sequences, respectively) carried out in 2 independent research labs in serum samples from 19 untreated NPC cases, 11 healthy community controls and 100 unaffected individuals from families in which 2 or more individuals were affected with NPC. EBV genomes were detectable in 68% of NPC cases by the EBV BamH1W assay and in 74% by the EBV polymerase assay (kappa = 0.64). Patients with stage III or IV disease had significantly higher EBV load compared to those with stage I or II disease (p = 0.008). EBV DNA was detected in a single community control sample by the EBV BamH1W assay and in none of the samples by the EBV polymerase assay. Only one of 100 unaffected family members tested positive by both assays. An additional 14 were positive by only one of the 2 EBV load assays used and usually in only one of the duplicate wells tested, all with very low viral loads (3-50 copies/ml). In addition, EBV load did not correlate with EBV serology results (anti-VCA, anti-DNase, anti-EBNA-1) among these unaffected family members. In conclusion, our study suggests limited clinical utility of the EBV load test, in its current configuration, to screen individuals from high-risk families. Should a more sensitive or specific molecular assay be developed that is capable of detecting and distinguishing tumor-derived EBV genomes or gene products from true negatives, it could be evaluated as a possible screening tool for asymptomatic and early-stage NPC.
Asunto(s)
Anticuerpos Antivirales/análisis , Infecciones por Virus de Epstein-Barr/inmunología , Predisposición Genética a la Enfermedad , Genoma Viral , Neoplasias Nasofaríngeas/virología , Estudios de Casos y Controles , Infecciones por Virus de Epstein-Barr/epidemiología , Familia , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/patogenicidad , Humanos , Neoplasias Nasofaríngeas/epidemiología , Neoplasias Nasofaríngeas/genética , Riesgo , Factores de Riesgo , Estudios Seroepidemiológicos , Taiwán/epidemiología , Carga ViralRESUMEN
Nasopharyngeal carcinoma (NPC) is an Epstein-Barrvirus (EBV)-associated malignancy. Previous studies have shown that NPC is associated with specific human leukocyte antigen (HLA) alleles which function in adaptive immunity to present viral and other antigens to the immune system. The role of innate immunity in NPC development is unknown. To determine whether innate immunity is associated with NPC, a case-control study was conducted among 295 Taiwanese NPC cases (99% EBV seropositive) and 252 community controls (29% EBV seropositive). Using high-resolution genotyping, we evaluated the variation of HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) alleles. Located on the surface of natural killer (NK) cells and a subset of T cells, inhibitory KIRs diminish NK cytolysis of target cells upon binding to their HLA class I ligands and activating KIRs are thought to stimulate NK destruction of target cells. Our results suggest that an increasing number of activating KIRs may be associated with increasing NPC risk, particularly in individuals seropositive for anti-EBV antibodies known to be linked to NPC susceptibility (P(trend) = 0.07). Among EBV-seropositive individuals, carriers of > or =5 activating KIRs had a 3.4-fold increased risk of disease (95% confidence interval, 0.74-15.7) compared with individuals with no functional activating KIRs. In contrast, there was no clear evidence of risk associated with increasing numbers of inhibitory KIRs. When evaluating HLA-Cw alleles, we observed that carriers of HLA-Cw*0401 alleles were at a significantly reduced NPC risk (odds ratio, 0.46; 95% confidence intervals, 0.23-0.92), an effect that could not be explained by linkage disequilibrium with other NPC-associated HLA alleles. Our results suggest that KIR-mediated activation may be associated with NPC risk. As this finding is consistent with a recent report examining cervical cancer, a malignancy caused by human papillomavirus, the data raises the possibility that KIRs, and more generally innate immunity, may be involved in the pathogenesis of viral-associated cancers.
Asunto(s)
Carcinoma/genética , Genes MHC Clase I , Células Asesinas Naturales/inmunología , Neoplasias Nasofaríngeas/genética , Receptores Inmunológicos/análisis , Adulto , Anciano , Carcinoma/inmunología , Estudios de Casos y Controles , Femenino , Variación Genética , Genotipo , Humanos , Inmunidad Innata , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/inmunología , Factores de RiesgoRESUMEN
A study of nasopharyngeal carcinoma (NPC) families with two or more affected members was conducted in Taiwan (265 families with 2,444 individuals, 502 affected and 1,942 unaffected) to determine the association between NPC and potential etiologic factors in NPC high-risk families. Similar to results from a previous case-control study in Taiwan, Guangdong salted fish consumption during childhood, exposure to wood, and betel nut consumption were all associated with elevated NPC risk using conditional logistic regression, although these associations were not as strong as in the case-control study possibly due to shared environment among family members. Risk associated with cumulative wood exposure and salted fish consumption before age 10 was stronger in families with early NPC age-onset [odds ratio (OR(wood)), 5.10; 95% confidence interval (95% CI), 1.50-17.34; OR(fish), 3.94; 95% CI, 1.47-10.55] or three or more affected members (OR(wood), 4.41; 95% CI, 1.58-12.30; OR(fish), 4.27; 95% CI, 1.10-16.47). In contrast, a tendency for elevated risk was noted for betel nut use in late age-onset families (OR, 2.44; 95% CI, 1.16-5.13) and the CYP2E1 c2 allele in families with less than three affected members (OR, 2.06; 95% CI, 1.04-3.35). Risk estimates associated with these exposures were similar when the analyses were restricted to EBV-seropositive subjects. To better adjust for degree of relationship among family members and residual genetic correlations, we also calculated ORs using a variance components model. The results from the two methods were similar indicating that the risk estimates from conditional logistic regression were unbiased.
Asunto(s)
Areca/efectos adversos , Dieta , Exposición a Riesgos Ambientales/efectos adversos , Neoplasias Nasofaríngeas/etiología , Adolescente , Adulto , Niño , Métodos Epidemiológicos , Femenino , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/genética , Sistema de Registros , Factores de Riesgo , Encuestas y Cuestionarios , Taiwán/epidemiologíaRESUMEN
Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.
Asunto(s)
Anticuerpos Antivirales/análisis , Carcinoma/virología , Infecciones por Virus de Epstein-Barr/inmunología , Predisposición Genética a la Enfermedad , Inmunoglobulina A/análisis , Neoplasias Nasofaríngeas/virología , Adolescente , Adulto , Anciano , Carcinoma/genética , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/genética , Linaje , Factores de Riesgo , Estudios Seroepidemiológicos , TaiwánRESUMEN
Nitrosamine consumption and polymorphisms in CYP2E1, the product of which is involved in the activation of nitrosamines into reactive intermediates, have been shown to be associated with nasopharyngeal carcinoma (NPC) risk. Given that reactive intermediates created during nitrosamine metabolism are capable of DNA damage, we further hypothesized that differences between individuals in their ability to repair DNA damage might be important in NPC pathogenesis. To evaluate this hypothesis, this study focused on effects of genetic polymorphisms of DNA repair genes hOGG1 and XRCC1 on the development of NPC. We conducted a case-control study to investigate the genotypes of 334 patients with NPC and 283 healthy community controls matched by sex, age, and residence. The PCR-based RFLP assay was used to identify genetic polymorphisms. After adjustment for sex, age, and ethnicity, the odds ratio (OR) of developing NPC for hOGG1 codon 326 genotypes of Ser/Cys and Cys/Cys compared with the Ser/Ser genotype was 1.6 (95% CI, 1.0-2.6). For XRCC1 codon 280 genotypes of Arg/His and His/His compared with the Arg/Arg genotype, the OR was 0.64 (95% CI, 0.43-0.96). Among subjects with putative high-risk genotypes for both hOGG1 and XRCC1, the OR was 3.0 (95% CI, 1.0-8.8). Furthermore, subjects with putative high-risk genotypes for hOGG1, XRCC1, and CYP2E1 had an OR of disease of 25 (95% CI, 3.5-177). Polymorphisms of the DNA repair genes hOGG1 (codon 326) and XRCC1 (codon 280) are associated with an altered risk of NPC. Carriers of multiple putative high-risk genotypes have the highest risk of developing NPC.
Asunto(s)
Carcinoma/genética , Daño del ADN , ADN Glicosilasas/genética , Reparación del ADN , Proteínas de Unión al ADN/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo Genético , Adulto , Carcinoma/fisiopatología , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/fisiopatología , Oportunidad Relativa , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XAsunto(s)
Arilamina N-Acetiltransferasa/genética , Carcinoma/genética , Citocromo P-450 CYP1A1/genética , Glutatión Transferasa/genética , Isoenzimas/genética , Neoplasias Nasofaríngeas/genética , Polimorfismo Genético/genética , Alelos , Biomarcadores de Tumor/genética , Carcinoma/epidemiología , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Marcadores Genéticos/genética , Genotipo , Gutatión-S-Transferasa pi , Humanos , Masculino , Neoplasias Nasofaríngeas/epidemiología , Factores de Riesgo , Estadística como Asunto , Taiwán/epidemiologíaRESUMEN
BACKGROUND: Nasopharyngeal carcinoma (NPC), which occurs at a disproportionately high rate among Chinese individuals, is associated with Epstein-Barr virus (EBV). Human leukocyte antigen (HLA) polymorphisms appear to play a role in NPC, because they are essential in the immune response to viruses. We used high-resolution HLA genotyping in a case-control study in Taiwan to systematically evaluate the association between various HLA alleles and NPC. METHODS: We matched 366 NPC case patients to 318 control subjects by age, sex, and geographic residence. Participants were interviewed and provided blood samples for genotyping. High-resolution (polymerase chain reaction-based) genotyping of HLA class I (A and B) and II (DRB1, DQA1, DQB1, and DPB1) genes was performed in two phases. In phase I, 210 case patients and 183 control subjects were completely genotyped. In phase II, alleles associated with NPC in the phase I analysis were evaluated in another 156 case patients and 135 control subjects. Extended haplotypes were inferred. RESULTS: We found a consistent association between HLA-A*0207 (common among Chinese but not among Caucasians) and NPC (odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.5 to 3.5) but not between HLA-A*0201 (most common HLA-A2 allele in Caucasians) and NPC (OR = 0.79, 95% CI = 0.55 to 1.2). Individuals with HLA-B*4601, which is in linkage disequilibrium with HLA-A*0207, had an increased risk for NPC (OR = 1.8, 95% CI = 1.2 to 2.5) as did individuals with HLA-A*0207 and HLA-B*4601 (OR = 2.8, 95% CI = 1.7 to 4.4). Individuals homozygous for HLA-A*1101 had decreased risks for NPC (OR = 0.24, 95% CI = 0.13 to 0.46). The extended haplotype HLA-A*3303-B*5801/2-DRB1*0301-DQB1*0201/2-DPB1*0401, specific to this ethnic group, was associated with a statistically significantly increased risk for NPC (OR = 2.6, 95% CI = 1.1 to 6.4). CONCLUSIONS: The restriction of the association of HLA-A2 with NPC to HLA-A*0207 probably explains previously observed associations of HLA-A2 with NPC among Chinese but not Caucasians. The extended haplotypes associated with NPC might, in part, explain the higher rates of NPC in this ethnic group.