RESUMEN
BACKGROUND: Cervical cancer is caused primarily by human papillomaviruses (HPV). The polymorphism rs1042522 at codon 72 of the TP53 tumour-suppressor gene has been investigated as a genetic cofactor. More than 80 studies were done between 1998 and 2006, after it was initially reported that women who are homozygous for the arginine allele had a risk for cervical cancer seven times higher than women who were heterozygous for the allele. However, results have been inconsistent. Here we analyse pooled data from 49 studies to determine whether there is an association between TP53 codon 72 polymorphism and cervical cancer. METHODS: Individual data on 7946 cases and 7888 controls from 49 different studies worldwide were reanalysed. Odds ratios (OR) were estimated using logistic regression, stratifying by study and ethnic origin. Subgroup analyses were done for infection with HPV, ethnic origin, Hardy-Weinberg equilibrium, study quality, and the material used to determine TP53 genotype. FINDINGS: The pooled estimates (OR) for invasive cervical cancer were 1.22 (95% CI 1.08-1.39) for arginine homozygotes compared with heterozygotes, and 1.13 (0.94-1.35) for arginine homozygotes versus proline homozygotes. Subgroup analyses showed significant excess risks only in studies where controls were not in Hardy-Weinberg equilibrium (1.71 [1.21-2.42] for arginine homozygotes compared with heterozygotes), in non-epidemiological studies (1.35 [1.15-1.58] for arginine homozygotes compared with heterozygotes), and in studies where TP53 genotype was determined from tumour tissue (1.39 [1.13-1.73] for arginine homozygotes compared with heterozygotes). Null results were noted in studies with sound epidemiological design and conduct (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes), and studies in which TP53 genotype was determined from white blood cells (1.06 [0.87-1.29] for arginine homozygotes compared with heterozygotes). INTERPRETATION: Subgroup analyses indicated that excess risks were most likely not due to clinical or biological factors, but to errors in study methods. No association was found between cervical cancer and TP53 codon 72 polymorphism when the analysis was restricted to methodologically sound studies. FUNDING: German Research Foundation (DFG).
Asunto(s)
Genes p53 , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Neoplasias del Cuello Uterino/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/virología , Adulto JovenRESUMEN
A common polymorphism at codon 72 of exon 4 encoding either arginine or proline has been shown to confer a susceptibility to the development of skin tumor in renal transplant recipients. Moreover, this polymorphism may affect proteolytic degradation of p53 promoted by E6 protein from mucosal human papillomaviruses and represent a risk factor for human-papillomavirus-induced carcinogenesis. In this study, we analyzed the human papillomavirus presence and the TP53 allele distribution in cutaneous squamous cell carcinoma of renal transplant recipients and immunocompetent patients. Fifty-three squamous cell carcinomas from 40 renal transplant recipients, 50 benign epithelial skin lesions from 50 renal transplant recipients with no history of skin cancer, 51 squamous cell carcinomas from immunocompetent patients, and 29 blood samples from immunocompetent individuals without skin cancer were investigated. Human papillomavirus DNA was detected using polymerase chain reaction performed with two pairs of primers (MY09-MY11 and FAP59-FAP64). TP53 allele distribution was studied by denaturing gradient gel electrophoresis assay, followed by sequencing analysis. Human papillomavirus DNA was detected in 64% of squamous cell carcinoma and 79% of benign epithelial lesions from renal transplant recipients (NS) and only in 37% of squamous cell carcinoma from immunocompetent patients (p < 0.05). Mucosal oncogenic human papillomavirus types were predominant in squamous cell carcinoma from both renal transplant recipients and immunocompetent patients. Rate of arginine homozygosity in squamous cell carcinoma from renal transplant recipients was significantly higher (83%) than in immunocompetent patients with or without squamous cell carcinoma (60% and 59%, respectively). Our results suggest that TP53 arginine/arginine genotype could represent a potential risk factor for the development of squamous cell carcinoma in renal transplant recipients compared to immunocompetent patients. No association between TP53 arginine/arginine genotype and human papillomavirus status could be determined, however.
Asunto(s)
Carcinoma de Células Escamosas/genética , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/genética , Neoplasias Cutáneas/genética , Proteína p53 Supresora de Tumor/genética , Infecciones Tumorales por Virus/genética , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/virología , Células Epiteliales/patología , Exones , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Inmunocompetencia , Trasplante de Riñón/inmunología , Papillomaviridae/genética , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/patología , Polimorfismo de Nucleótido Simple , Prevalencia , Factores de Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/virología , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/patologíaRESUMEN
OBJECTIVE: To investigate the codon 72 TP53 polymorphism in women from eastern France with normal or abnormal cervical cytology. STUDY DESIGN: We analyzed the TP53 allele distribution by denaturant gradient gel electrophoresis assay and the human papillomaviruses (HPV) infection in 138 cervical smears: 50 normal, 20 atypical squamous cells of undetermined significance, 40 low grade squamous intraepithelial lesions, 28 high grade squamous intraepithelial lesions. RESULTS: The viral DNA prevalence increased with cytological abnormalities. The rates of arginine (Arg) and proline (Pro) homozygosity and Arg/Pro heterozygosity were 49, 0.72, and 51%, respectively. No association was found between HPV status and TP53 polymorphism. No differences were observed in the frequency of the TP53 genotypes according to cytology. CONCLUSION: The TP53 Arg/Arg genotype does not appear to represent a risk factor in the progression of HPV associated cervical lesions. We were not able to confirm that the TP53 genotype increases the susceptibility to be infected by HPV or to develop HGSIL, and a fortiori invasive carcinoma of the cervix.
Asunto(s)
Exones , Genes p53/genética , Papillomaviridae/aislamiento & purificación , Polimorfismo Genético , Neoplasias del Cuello Uterino/genética , Adolescente , Adulto , Anciano , ADN Viral/análisis , Femenino , Francia , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Persona de Mediana Edad , Papillomaviridae/genética , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa , Lesiones Precancerosas/genética , Lesiones Precancerosas/virología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Frotis VaginalRESUMEN
The ARF tumor suppressor controls a well-described p53/Mdm2-dependent oncogenic stress checkpoint. In addition, ARF has recently been shown to localize to mitochondria, and to induce autophagy; however, this has never before been demonstrated for endogenous ARF, and the molecular basis for this activity of ARF has not been elucidated. Using an unbiased mass spectrometry-based approach, we show that mitochondrial ARF interacts with the Bcl2 family member Bcl-xl, which normally protects cells from autophagy by inhibiting the Beclin-1/Vps34 complex, which is essential for autophagy. We find that increased expression of ARF decreases Beclin-1/Bcl-xl complexes in cells, thereby providing a basis for ARF-induced autophagy. Our data also indicate that silencing p53 leads to high levels of ARF and increased autophagy, thereby providing a possible basis for the finding by others that p53 inhibits autophagy. The combined data support the premise that ARF induces autophagy in a p53-independent manner in part by virtue of its interaction with Bcl-xl.
Asunto(s)
Autofagia/fisiología , Proteína p14ARF Supresora de Tumor/fisiología , Proteína bcl-X/metabolismo , Western Blotting , Línea Celular Tumoral , Humanos , Inmunoprecipitación , Proteína p14ARF Supresora de Tumor/metabolismoRESUMEN
p14/p19ARF (ARF) is a tumor suppressor gene that is frequently mutated in human cancer. ARF has multiple tumor suppressor functions, some of which are mediated by signaling to p53. Surprisingly, a significant fraction of human tumors retain persistently high levels of ARF, suggesting that ARF may possess a prosurvival function. We show that ARF protein is markedly up-regulated in cells exposed to nutrient starvation. Cells with silenced ARF show reduced autophagy and reduced viability when placed under conditions of starvation. We show for the first time that ARF silencing can limit the progression of some tumors, such as lymphoma, but not others, such as E1A/Ras-induced tumors. Specifically, myc-driven lymphomas with mutant p53 tend to overexpress ARF; we show that silencing ARF in these tumors greatly impedes their progression. These data are the first to show that ARF can act in a p53-independent manner to promote the progression of some tumors.