RESUMEN
Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.
Asunto(s)
Predisposición Genética a la Enfermedad , Neoplasias Pancreáticas , Humanos , Estudios Retrospectivos , Estudios Prospectivos , Mutación de Línea Germinal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologíaRESUMEN
BACKGROUND: Since the last recommendations, up to 2500 new references had been published on that topic. METHODOLOGY: On the behalf of the health Minister, the Ad Hoc Committee consisted of 13 experts carried out a first version revisited by five additional experts who critically analyzed the first version of the report. MAIN UPDATING: Breast and ovarian cancer seem to be associated with fewer deleterious mutations of BRCA1 and BRCA2 than previously thought. The screening of ovarian cancer is still not an attractive option while in contrast MRI may be soon for these young women with dense breast, the recommended option for breast cancer screening. The effectiveness of prophylactic surgeries is now well established. French position is to favor such surgeries with regard to a quality of life in line with the expected benefit, and providing precise and standardized process described in the recommendation. CONCLUSIONS: Due to methodological flaws, the low power and a short follow-up of the surveys, this statement cannot however aspire to a high stability.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias Ováricas/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/terapia , Confidencialidad , Femenino , Francia/epidemiología , Genes BRCA1 , Genes BRCA2 , Genotipo , Humanos , Mastectomía , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/terapia , Fenotipo , Relaciones Médico-PacienteRESUMEN
BACKGROUND: This article presents analysis of clinical and family data for 239 patients with childhood soft tissue sarcoma (STS) treated at the Institut Gustave Roussy in Villejuif. METHODS: A molecular study was performed to detect germline p53 mutations in the 44 families in which at least 1 relative developed cancer before the age of 46 or in which the proband had a second neoplasm. Mutations were found in five families. Standardized incidence ratio calculation and segregation analysis were used to study cancer occurrence in 4448 relatives, including first- and second-degree relatives and first cousins. RESULTS: An excess of brain tumors was observed in all relatives, and of breast carcinoma and STS in first-degree relatives of patients with STS. An excess of breast carcinoma was observed only in young mothers of patients with rhabdomyosarcoma. This excess might be mostly linked to the presence of a germline p53 mutation because it was no more significant when excluding families in which such a mutation existed. No association between breast carcinoma in the mother and rhabdomyosarcoma of the genitourinary tract in the proband was observed. This should be kept in mind when developing a screening strategy for breast carcinoma in mothers of patients with STS. Segregation analysis showed evidence for transmission of an autosomal dominant gene with complete penetrance by the age of 84. The genetic component was explained primarily by p53 germline mutations. CONCLUSIONS: These results show that most relatives of patients with STS are at the same risk for cancer as the general population.
Asunto(s)
Genes p53/genética , Mutación de Línea Germinal , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Adulto , Neoplasias Óseas/genética , Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Niño , Susceptibilidad a Enfermedades , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Linaje , Factores de RiesgoRESUMEN
Glucocorticoid-induced apoptosis in the murine interleukin-2-dependent T-cell line CTLL-2 and in freshly isolated thymocytes was studied. It was demonstrated here that in CTLL-2 cells, dexamethasone (methyl in position 16 alpha) was more efficient in inducing apoptosis than betamethasone (methyl in position 16 beta) or triamcinolone (hydroxyl in position 16). In contrast, no such difference between these three molecules was found in murine thymocytes. In addition, we showed that glucocorticoid-induced apoptosis on the two models was mediated through interaction with the glucocorticoid receptor and did not occur in the presence of inhibitors of transcription, translation or an endonuclease-inhibitor. Furthermore, in CTLL-2 cells, apoptosis took place in the presence of EGTA whereas it was prevented in murine thymocytes, thus indicating that calcium plays a different role in these two models. Finally, higher concentrations of interleukin-2 were needed to protect CTLL-2 cells against dexamethasone-induced apoptosis than that induced by betamethasone or triamcinolone. Thus, structural differences at position 16 of the steroid nucleus correlate with a different apoptosis-inducing activity by glucocorticoids which, however, is only evidenced in the calcium-independent CTLL-2 model.
Asunto(s)
Apoptosis/efectos de los fármacos , Betametasona/farmacología , Dexametasona/farmacología , Linfocitos T/efectos de los fármacos , Triamcinolona/farmacología , Animales , Betametasona/química , Línea Celular , ADN/efectos de los fármacos , Dexametasona/química , Interleucina-2/farmacología , Ratones , Relación Estructura-Actividad , Linfocitos T/citología , Timo/citología , Timo/efectos de los fármacos , Triamcinolona/químicaRESUMEN
Germline p53 mutations have been detected in approximately half of the families affected by the Li-Fraumeni syndrome (LFS), in which they are believed to represent the genetic status predisposing to multiple cancers. Failure to detect mutations in the other half of LFS families suggests that sequence analysis, which has been limited to the p53 gene coding region, have overlooked other genetic events lying outside of this region or/and that alterations in other gene(s) than p53 may also lead to the syndrome. In this report, we present the evidence that a single base pair deletion in the p53 coding sequence, leading to premature signal termination of translation, generates a null allele by preventing transport of mutant allele mRNAs into the cytoplasm. This allelic exclusion which confers a status of unizygote vis-à-vis the wild-type p53 gene to individuals who carry the mutant allele, leads to predisposition to multiple cancers in a Li-Fraumeni family. Thus, the loss of the wild-type p53 allele appears as the rate limiting step in tumor induction.
Asunto(s)
Alelos , Genes p53 , Mutación de Línea Germinal , Síndrome de Li-Fraumeni/genética , Biosíntesis de Proteínas , Secuencia de Bases , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Empalme del ARN , ARN Mensajero/genética , Células Tumorales CultivadasRESUMEN
The aim of our study was to analyze the correlation between tumor-cell kinetics measured in vivo and p53 gene expression in a series of 49 oropharyngeal cancers. The duration of the S phase (TS), the labelling index (LI) and the potential doubling time (Tpot) were obtained by flow-cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine into patients. An adjacent section of the same samples was studied by immunohistochemistry for the detection of p53 protein. Over-expression of the p53 protein, as defined by strong p53 immunostaining of tumor nuclei, was found in 23/49 of the samples. Aneuploid tumors showed a higher LI, a shorter Tpot and a higher proportion of p53 gene over-expression. A significant correlation was seen between p53 over-expression and short Tpots. Indeed 87.5% of the tumors with a very short Tpot (< or = 3 days) had p53 over-expression, as compared with 27% of tumors with a longer Tpot (> 3 days). Our data strongly suggest that over-expression of the p53 gene is associated with rapid tumor-cell proliferation in this type of cancer.
Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Genes p53 , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patología , Anciano , Bromodesoxiuridina/metabolismo , Carcinoma de Células Escamosas/química , Ciclo Celular , División Celular/fisiología , ADN de Neoplasias/metabolismo , Femenino , Citometría de Flujo , Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/química , Estudios Prospectivos , Fase S/fisiología , Proteína p53 Supresora de Tumor/análisisRESUMEN
p53 antibodies have been found in sera of patients with breast and lung carcinomas and in children with B-lymphomas. We report here the presence of p53 antibodies in sera of patients with 11 different types of cancer. The frequency of seropositives for p53 varied among the different types of cancer, but a correlation with the frequency of p53 gene alteration was established. Using a powerful peptide enzyme-linked immunosorbent assay, we demonstrated that the immune response of patients with p53 antibodies was restricted to a small subset of peptides localized in the amino and carboxy termini of p53, whatever the type of cancer. Given the similarities of the patterns of immune responses in patients with p53 antibodies and animals hyperimmunized with human p53, we propose that the p53 humoral response is the result of a self-immunization process which is itself the consequence of p53 protein accumulation in tumor cells.
Asunto(s)
Anticuerpos/sangre , Linfocitos B/inmunología , Epítopos Inmunodominantes/análisis , Neoplasias/inmunología , Proteína p53 Supresora de Tumor/inmunología , Secuencia de Aminoácidos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Datos de Secuencia Molecular , Conformación Proteica , Proteína p53 Supresora de Tumor/químicaRESUMEN
We analyzed the status of retinoblastoma and p53 genes in 10 human hepatoma cell lines. Polyclonal anti-peptide antibodies generated against peptides homologous to COOH-terminal and leucine-zipper domains of the retinoblastoma protein allowed us to identify two cell lines (Hep 3B and FOCUS) with abnormal expression. The same cell lines have both lacked p53 expression. In contrast to the retinoblastoma gene, the expression of the p53 gene was abnormal in six additional cell lines. Indeed, only the Hep G2 hepatoblastoma cell line (and its derivative Hep G2/2215) appeared to have normal p53 and retinoblastoma gene expression. Our studies indicate that p53 abnormalities are common but retinoblastoma gene aberrations are rare in human hepatoma cell lines.
Asunto(s)
Carcinoma Hepatocelular/genética , Expresión Génica , Genes de Retinoblastoma , Genes p53 , Neoplasias Hepáticas/genética , Secuencia de Aminoácidos , Northern Blotting , Cromosomas Humanos Par 17 , Humanos , Técnicas de Inmunoadsorción , Datos de Secuencia Molecular , Mutación , ARN Mensajero/análisis , Proteína de Retinoblastoma/análisis , Proteína de Retinoblastoma/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de TumorRESUMEN
This report describes a new polymorphism, in intron 3 of the p53 gene, which consists of a single repeat of 16 nucleotides, absent in the published wild-type p53 gene sequence. In the Caucasian population tested (n = 82), 28% of individuals were heterozygotes for this polymorphism. Using PCR-based analysis, we were able to demonstrate p53 allelic losses in three of six breast tumors from heterozygote patients tested.
Asunto(s)
Genes p53 , Polimorfismo Genético , Secuencias Repetitivas de Ácidos Nucleicos , Secuencia de Bases , Neoplasias de la Mama/genética , Exones , Femenino , Humanos , Intrones , Datos de Secuencia Molecular , Oligodesoxirribonucleótidos , Reacción en Cadena de la Polimerasa , Población Blanca/genéticaRESUMEN
Epidemiological studies indicate that environmental factors are more important for cancer development than inherited factors. However, clinical observations such as familial cancer clustering, constitute compelling evidence to the existence of inherited susceptibility to cancer. Few cancer-predisposing genes have been identified so far, by hard laboratory work and with the help of molecular biology tools. The predisposing genes that have been cloned can be used for DNA-based diagnosis. Genes inherited in altered form in familial cancers are the same genes that are altered in somatic cells of individuals with sporadic cancers. Identification of cancer genes through the study of rare families in which susceptibility to cancer is inherited, could have important consequences for diagnosis and treatment of common cancers.
Asunto(s)
Neoplasias/genética , Síndromes Neoplásicos Hereditarios/genética , Transformación Celular Neoplásica , Genes/genética , Humanos , Neoplasias/epidemiologíaRESUMEN
Hepatocellular carcinoma (HCC) is a prevalent cancer in sub-Saharan Africa and eastern Asia. Hepatitis B virus and aflatoxins are risk factors for HCC, but the molecular mechanism of human hepatocellular carcinogenesis is largely unknown. Abnormalities in the structure and expression of the tumour-suppressor gene p53 are frequent in HCC cell lines, and allelic losses from chromosome 17p have been found in HCCs from China and Japan. Here we report on allelic deletions from chromosome 17p and mutations of the p53 gene found in 50% of primary HCCs from southern Africa. Four of five mutations detected were G----T substitutions, with clustering at codon 249. This mutation specificity could reflect exposure to a specific carcinogen, one candidate being aflatoxin B1 (ref. 7), a food contaminant in Africa, which is both a mutagen that induces G to T substitution and a liver-specific carcinogen.
Asunto(s)
Carcinoma Hepatocelular/genética , Genes Supresores de Tumor , Neoplasias Hepáticas/genética , Proteína p53 Supresora de Tumor/genética , Aflatoxinas/toxicidad , África Austral , Secuencia de Bases , Deleción Cromosómica , Cromosomas Humanos Par 17 , Sondas de ADN , Exones , Humanos , Datos de Secuencia Molecular , Mutación , Oligonucleótidos/química , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.
Asunto(s)
Ciclo Celular , Osteosarcoma/patología , Proteína p53 Supresora de Tumor/fisiología , Secuencia de Aminoácidos , Línea Celular , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Transfección , Proteína p53 Supresora de Tumor/genéticaRESUMEN
There is little information regarding the molecular mechanisms of hepatocarcinogenesis. We studied the p53 gene at the DNA, RNA, and protein level in seven human hepatocellular carcinoma (HCC)-derived cell lines; six of seven showed p53 abnormalities. By Southern blotting, the p53 gene was found to be partially deleted in Hep 3B and rearranged in SK-HEP-1 cells. Transcripts of the p53 gene were undetectable in Hep 3B as well as in FOCUS cells that had no apparent deletion or rearrangement of the p53 gene. Immunoprecipitation after [35S]methionine labeling of HCC cells demonstrated that p53 protein was absent in Hep 3B and FOCUS and reduced in concentration in PLC/PRF/5 cells. p53 synthesized by Mahlavu cells showed a slower migration on SDS/polyacrylamide gels suggesting it was an abnormal protein. In Huh7 cells, p53 protein had a prolonged half-life leading to its accumulation in the nuclei; increased levels of p53 protein were also found by immunoblotting. The p53 gene and its expression appeared to be unaltered in the hepatoblastoma-derived Hep G2 cell line. We found that the loss of p53 expression did not occur as a late in vitro event in the FOCUS cell line because p53 protein was also nondetectable at an early passage. We conclude that the loss of p53 expression or the presence of abnormal forms of the protein are frequently associated with HCC cell lines. These observations suggest that alterations in p53 may be important events in the transformation of hepatocytes to the malignant phenotype.
Asunto(s)
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteínas Oncogénicas/genética , Fosfoproteínas/genética , Southern Blotting , Línea Celular , Expresión Génica , Humanos , Hígado/metabolismo , Peso Molecular , Proteínas Nucleares/genética , Proteínas Oncogénicas/aislamiento & purificación , Fosfoproteínas/aislamiento & purificación , ARN Neoplásico/genética , Valores de Referencia , Proteína p53 Supresora de TumorRESUMEN
A Mr 50,000 cell surface protein antigen (p50) was identified on a human hepatocellular carcinoma derived cell line (FOCUS) by two monoclonal antibodies (SF 31 and SF 90). This antigen was subsequently shown to be expressed in vivo in human hepatocellular carcinoma. All 18 tumors tested by Western immunoblotting demonstrated high levels of p50 with undetectable amounts observed in the adjacent normal liver counterparts. Further characterization revealed that p50 is a monomeric polypeptide with a neutral pI (6.5-7.2) and appears not to be glycosylated. The cellular localization was determined by direct antibody binding to intact cells, immunoprecipitation of 125I-labeled cell surface proteins, and Western immunoblotting of subcellular fractions. p50 was found on the cell surface as well as in the cytoplasm. In vitro monoclonal antibody binding studies indicate that the protein is expressed in all human malignant cells (n = 34) tested thus far regardless of the embryonic tissue of origin and the degree of differentiation. p50 was present at very low levels in normal tissues with the notable exception of high expression in adrenal glands. The protein is conserved in mammalian evolution since a similar protein was also found in bovine adrenals. The molecular characteristics and the pattern of expression of p50 indicate that this normal adrenal protein is associated with the transformed phenotype.