RESUMO
DICER1-related tumors occur hereditary or sporadically, with high-grade malignancies sharing clinicopathological and (epi)genetic features. We compared 4 pleuropulmonary blastomas (PPBs) and 6 sarcomas by mutation analysis, whole transcriptome sequencing and methylation profiling. 9/10 patients were female. PPB patients were 0-4 years. 3/4 were alive; 2 without disease. One patient died of metastatic disease (median follow-up, 16 months). Sarcoma patients were 16-56 years. Locations included: uterine cervix/corpus (3/1), soft tissue back/shoulder (1) and paravertebral (1). 5/6 patients were alive; 2 developed metastases: intracranial (1) and lung and kidney (1) (median follow-up, 17 months). The deceased patient previously had a PPB and a Sertoli-Leydig cell tumor. Histologically, tumors showed atypical primitive-looking cells with incomplete rhabdomyoblastic differentiation and cartilage (n = 5). Immunohistochemistry demonstrated desmin- (n = 9/10), myogenin- (n = 6/10) and keratin positivity (n = 1/1). Eight cases harbored biallelic DICER1 mutations with confirmed germline mutations in 4 cases. Two cases showed a monoallelic mutation. By RNA expression- and methylation profiling, distinct clustering of our cases was seen demonstrating a close relationship on (epi)genetic level and similarities to embryonal rhabdomyosarcoma. In conclusion, this study shows overlapping morphological, immunohistochemical and (epi)genetic features of PPBs and DICER1-associated high-grade sarcomas, arguing that these neoplasms form a spectrum with a broad clinicopathological range.
Assuntos
Blastoma Pulmonar , Rabdomiossarcoma Embrionário , Neoplasias de Tecidos Moles , Feminino , Humanos , Masculino , RNA Helicases DEAD-box/genética , Desmina , Queratinas , Mutação , Miogenina , Blastoma Pulmonar/genética , Blastoma Pulmonar/patologia , Rabdomiossarcoma Embrionário/genética , Ribonuclease III/genética , RNARESUMO
Cancer incidence data are generally presented in terms of primary site, but this method is inappropriate for cancers in young persons. We have used a morphology-based classification system to produce national incidence rates for cancers in persons aged 12-24 years by detailed diagnostic sub-type. The overall incidence rates for malignant disease in young persons aged 12-14, 15-19 and 20-24 years were 10.1, 14.4 and 22.6 per 100000 population, respectively. The three most frequent cancer types in 12-14-year-olds were leukaemias, lymphomas and central nervous system (CNS) tumours. In 15-19-year-olds, lymphomas were most frequent and leukaemias second with carcinomas third. In 20-24-year-olds, lymphomas were again most frequent, but carcinomas and germ cell tumours were second and third. There was also variation with age in the ratios of rates in males and females. These changing incidence patterns have aetiological implications and provide clues for future hypothesis-based research.
Assuntos
Neoplasias/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Criança , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Leucemia/epidemiologia , Linfoma/epidemiologia , Masculino , Neoplasias/patologia , Distribuição de Poisson , Análise de Regressão , Fatores de RiscoRESUMO
Cancer patients aged 15-24 years have distinct special needs. High quality cancer statistics are required for service planning. Data presented by primary site are inappropriate for this age group. We have developed a morphology-based classification and applied it to national cancer registration data for England 1979-1997. The study included 25,000 cancers and 134 million person-years at risk. Rates for each diagnostic group by age, sex and time period (1979-83, 1984-87, 1988-92, 1993-1997) were calculated. Overall rates in 15-19 and 20-24-year-olds were 144 and 226 per million person-years respectively. Lymphomas showed the highest rates in both age groups. Rates for leukaemias and bone tumours were lower in 20-24 year olds. Higher rates for carcinomas, central nervous system tumours, germ-cell tumours, soft tissue sarcomas and melanoma were seen in the older group. Poisson regression showed incidence increased over the study period by an average of 1.5% per annum (P<0.0001). Significant increases were seen in non-Hodgkins lymphoma (2.3%), astrocytoma (2.3%), germ-cell tumours (2.3%), melanoma (5.1%) and carcinoma of the thyroid (3.5%) and ovary (3.0%). Cancers common in the elderly are uncommon in adolescents and young adults. The incidence of certain cancers in the latter is increasing. Future studies should be directed towards aetiology.
Assuntos
Neoplasias/classificação , Neoplasias/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adolescente , Adulto , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Análise de Regressão , Estudos Retrospectivos , Medição de RiscoRESUMO
Tumour and normal tissue from 41 male cases of Wilms' tumour were screened to determine the presence of sequence variants in the glypican 3 (GPC3) gene. Two non-conservative single base changes were present in tumour tissue only. These findings imply a possible role for GPC3 in Wilms' tumour development.
Assuntos
Proteoglicanas de Heparan Sulfato/genética , Neoplasias Renais/genética , Mutação/genética , Tumor de Wilms/genética , Primers do DNA/química , Glipicanas , Humanos , Masculino , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
To investigate whether infections or other environmental exposures may be involved in the aetiology of childhood central nervous system tumours, we have analysed for space-time clustering and seasonality using population-based data from the North West of England for the period 1954 to 1998. Knox tests for space-time interactions between cases were applied with fixed thresholds of close in space, <5 km, and close in time, <1 year apart. Addresses at birth and diagnosis were used. Tests were repeated replacing geographical distance with distance to the Nth nearest neighbour. N was chosen such that the mean distance was 5 km. Data were also examined by a second order procedure based on K-functions. Tests for heterogeneity and Edwards' test for sinusoidal variation were applied to examine changes of incidence with month of birth or diagnosis. There was strong evidence of space-time clustering, particularly involving cases of astrocytoma and ependymoma. Analyses of seasonal variation showed excesses of cases born in the late Autumn or Winter. Results are consistent with a role for infections in a proportion of cases from these diagnostic groups. Further studies are needed to identify putative infectious agents.
Assuntos
Astrocitoma/etiologia , Neoplasias Encefálicas/etiologia , Ependimoma/etiologia , Infecções/complicações , Adolescente , Astrocitoma/epidemiologia , Astrocitoma/microbiologia , Declaração de Nascimento , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/microbiologia , Criança , Pré-Escolar , Ependimoma/epidemiologia , Ependimoma/microbiologia , Feminino , Geografia , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Estações do AnoRESUMO
BACKGROUND: There has been speculation that increasing trends in incidence of childhood central nervous system tumors and infant neuroblastoma in the United States have been due to diagnostic improvements or reporting changes. To investigate whether or not such trends could be explained in this way in the U.K., the authors used population-based data from Northwest England to analyze incidence trends in childhood solid tumors. METHODS: Cases were diagnosed during 1954-1998 and were grouped according to a morphology-based classification scheme. More than 95% of diagnoses were based on special histopathologic review. Tissue sections were retained, and diagnoses were rereviewed to ensure consistency in classification throughout the time period. Age-, gender- and period-specific incidence rates were calculated. Analyses were performed with chi-square tests and Poisson regression. RESULTS: There was an overall increase in the incidence of all childhood solid tumors of 0.9% each year. A temporal increase was found in childhood brain tumors characterized by, in particular, annual increases of 1% in pilocytic astrocytoma, 1% in primitive neuroectodermal tumors, and 2.3% in miscellaneous gliomas. The incidence of germ cell tumors increased at a rate of 2.6% each year. CONCLUSIONS: These increases could not be attributed to changes in diagnostic practice, and it is unlikely that the increases were due to changes in reporting practice. Further, the restriction of the increases to certain groups, with stable rates in others, argued against the changes being artifactual. The authors concluded that the increases in incidence were likely to be real.
Assuntos
Neoplasias/epidemiologia , Neoplasias do Sistema Nervoso Central/epidemiologia , Criança , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Distribuição de Poisson , RiscoRESUMO
The age-sex distributions and temporal trends in incidence of leukaemia and lymphoma from the Manchester Children's Tumour Registry (MCTR), 1954-1998, are reported. This 45-year study includes 1795 children, all of whom had a histologically and/or cytologically verified leukaemia or lymphoma. At the time of their diagnoses all the children were under 15 years of age and were resident in a geographically defined area of northwest England covered by the MCTR. Log-linear modelling identified significant linear increases in acute lymphoblastic leukaemia (ALL) (average annual increase 0.7%; P= 0.005) and in Hodgkin's disease (HD) (1.2%, P=0.04), but not in acute myeloid leukaemia (AML), nor in non-Hodgkin's lymphoma (NHL). The increase in ALL was most pronounced amongst males, aged 1-4 years, and is likely to be due to precursor B-cell leukaemias. The increases in ALL and HD are discussed in relation to current hypotheses suggesting a role for infection. Additionally, a non-linear cohort effect was identified for NHL (P= 0.008), which may indicate the involvement of environmental factors other than infection.
Assuntos
Leucemia/epidemiologia , Linfoma/epidemiologia , Doença Aguda , Adolescente , Fatores Etários , Criança , Pré-Escolar , Inglaterra/epidemiologia , Medidas em Epidemiologia , Feminino , Doença de Hodgkin/epidemiologia , Doença de Hodgkin/etiologia , Humanos , Incidência , Lactente , Leucemia/etiologia , Leucemia Mieloide/epidemiologia , Leucemia Mieloide/etiologia , Linfoma/etiologia , Linfoma não Hodgkin/epidemiologia , Linfoma não Hodgkin/etiologia , Masculino , Modelos Estatísticos , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Sistema de Registros , Fatores SexuaisRESUMO
The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values <0.02, were designated strongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocortical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas was moderately associated. Leukaemia and neuroblastoma were weakly associated. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.
Assuntos
Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni/epidemiologia , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Saúde da Família , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Lactente , Síndrome de Li-Fraumeni/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
Many polymorphisms have been reported in the TP53 gene. Some of these are within the coding region, and may affect the function of the p53 protein, others are within introns or non-coding regions, and their significance is unclear. Recently, a number of publications have claimed that polymorphisms within intron 6 are responsible for inherited predisposition to childhood malignancies, familial breast cancer, and Li-Fraumeni syndrome (LFS). We find no evidence for intron 6 sequence variants predisposing to LFS in our cohort of families and, furthermore, we show that some of the conclusions of other groups cannot be supported by data from our analysis.
Assuntos
Genes p53 , Íntrons , Síndrome de Li-Fraumeni/genética , Predisposição Genética para Doença , Humanos , Polimorfismo GenéticoRESUMO
Germline TP53 splicing mutations have been described infrequently (>2%) in the literature, however in a series of 40 patients and families identified by our group in which there are germline TP53 mutations, seven affect splicing (18%). The low figure reported in the literature might reflect the method of mutation detection, which in many studies does not include all splice junctions. These data indicate that a significant proportion of TP53 germline mutations are currently unrecognized. We have carried out detailed studies of the effects of the different mutations on splicing, and see distinct variations in the effects of the same mutation in different patients. Furthermore we have identified the usage of a non-consensus splice donor site in four families with an intron 4 splice donor mutation.
Assuntos
Processamento Alternativo/fisiologia , Genes p53/genética , Mutação em Linhagem Germinativa/fisiologia , Processamento Alternativo/genética , Linhagem Celular , Fibroblastos/fisiologia , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Íntrons , Síndrome de Li-Fraumeni/genética , Perda de Heterozigosidade , Linfócitos/fisiologia , Neoplasias/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/fisiologiaRESUMO
We have examined 11 cases of childhood adrenocortical tumours for copy number changes using comparative genomic hybridization (CGH). The changes seen are highly consistent between cases, and are independent of tumour type (carcinoma versus adenoma) or the presence of a germline TP53 mutation. The regions of chromosomal gain and loss identified in this study indicate the location of genes that are potentially important in the development and progression of childhood adrenocortical tumours. Finally, the copy number changes identified in childhood tumours are distinctly different to those seen in adult cases (Kjellman et al (1996) Cancer Res 56: 4219-4223), and we propose that this indicates that childhood tumours are of embryonal origin.
Assuntos
Adenoma/genética , Neoplasias do Córtex Suprarrenal/genética , Carcinoma/genética , Aberrações Cromossômicas , Adolescente , Criança , Pré-Escolar , DNA de Neoplasias/análise , Feminino , Genes p53 , Humanos , Lactente , Cariotipagem , Masculino , Mutação , Hibridização de Ácido NucleicoRESUMO
We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Alelos , Proteínas de Ligação a DNA , Genes p53/genética , Predisposição Genética para Doença/genética , Penetrância , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/metabolismo , Adulto , Idade de Início , Idoso , Proteínas de Transporte , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Síndrome de Li-Fraumeni/genética , Perda de Heterozigosidade/genética , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Dados de Sequência Molecular , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Proteínas de Neoplasias/análise , Proteínas Nucleares , Polimorfismo Conformacional de Fita Simples , Proteínas Proto-Oncogênicas/análiseRESUMO
The Li-Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li-Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.
Assuntos
Família , Síndrome de Li-Fraumeni/genética , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Saúde da Família , Feminino , Genótipo , Mutação em Linhagem Germinativa/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Linhagem , FenótipoRESUMO
We report a Li-Fraumeni syndrome family in which we have detected a splice acceptor mutation in intron 3 of TP53. The mutation affects one of the invariant residues at the splice acceptor site, as a result of which two aberrant transcripts are produced. A child with Wilms' tumour aged 3 years in this family was shown not to be a mutation carrier.
Assuntos
Neoplasias Renais/genética , Síndrome de Li-Fraumeni/genética , Mutação Puntual , Proteína Supressora de Tumor p53/genética , Tumor de Wilms/genética , Pré-Escolar , Éxons , Feminino , Mutação em Linhagem Germinativa , Heterozigoto , Humanos , Masculino , LinhagemRESUMO
Infection has long been suspected as a possible factor in the aetiology of leukaemia and lymphoma. If seasonal variation in the onset of disease could be shown in any of the diagnostic subgroups of leukaemia or lymphoma, this would provide supportive evidence of an aetiology linked to exposure to infection. All cases in the Manchester Children's Tumour Registry (aged 0-14 years at diagnosis) with acute lymphoblastic leukaemia (ALL), acute non-lymphocytic leukaemia (ANLL), Hodgkin's disease (HD) or non-Hodgkin lymphoma (NHL) between 1 January 1954 and 31 December 1996 were included in an analysis of seasonal variation in the month of first symptom and the month of diagnosis. Cases of common acute lymphoblastic leukaemia (c-ALL) diagnosed from 1979 onwards were also analysed separately. The groups considered for analysis were: all cases of ALL (n = 1070), ALL diagnosed between 18 and 95 months of age (n = 730), ALL diagnosed over 95 months of age (n = 266), c-ALL (n = 309), ANLL (n = 244), all infant acute leukaemias (ALL and ANLL under 18 months; n = 107), HD (n = 166) and NHL (n = 189). Using the Edwards method, both c-ALL and HD demonstrated significant seasonal variation (P = 0.037 and 0.001 respectively) in date of first symptom, with peaks occurring in November and December respectively. Using this method, no indication of seasonal variation was found in the other diagnostic groups for date of first symptom or in any of the diagnostic groups for date of diagnosis. For comparison with a previous study, a further analysis based on date of diagnosis for all ALL cases, using summer-winter ratios, showed a significant summer excess. These results provide supportive evidence for an infectious aetiology for c-ALL and HD, and possibly for all ALL, which warrants further investigation.
Assuntos
Doença de Hodgkin/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Linfoma não Hodgkin/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Estações do Ano , Adolescente , Criança , Pré-Escolar , Inglaterra/epidemiologia , Doença de Hodgkin/diagnóstico , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/diagnóstico , Linfoma não Hodgkin/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMO
We have previously reported on the analysis of TP53 coding mutations in 12 classic Li-Fraumeni syndrome (LFS) families plus 9 families that were Li-Fraumeni-like (LFL) families (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994). Mutations were found in 6 of 12 LFS families and in 1 of 9 LFL families. We have now extended these studies to include an additional nine LFS and nine LFL families, and TP53 mutations have been detected in eight of nine LFS families and in three of nine LFL families. Six of the new mutations described here are the same as those previously identified in other Li-Fraumeni families and are missense mutations at codons 245, 248, and 273 (in two families); a nonsense mutation at codon 209; and a mutation at the splice donor site in exon 4. The other five mutations are novel germ-line mutations and include missense mutations at codons 136 and 344, a 2-bp deletion within codon 191, a splice acceptor mutation in intron 3, and a 167-bp deletion of part of exon 1 and intron 1. In addition, we have detected a codon 175 mutation in a family previously reported as TP53 negative. To summarize all of the data from the families we have studied in this and our previous report (J. M. Birch et al., Cancer Res., 54: 1298-1304, 1994), mutations have been detected in 15 of 21 LFS families (71%) and in 4 of 18 LFL families (22%). These figures are somewhat higher than those previously reported by us and others for the frequency of TP53 mutations in LFS and LFL families. This could reflect our analysis of all 11 exons of TP53, including noncoding regions, as well as the use of direct sequencing rather than other less-sensitive mutation detection methods.
Assuntos
Genes p53/genética , Mutação em Linhagem Germinativa/genética , Síndrome de Li-Fraumeni/genética , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Regiões Promotoras Genéticas/genéticaRESUMO
We report the cytogenetic findings in a case of Pleuro-Pulmonary Blastoma of Childhood Type II. This is a rare intrathoracic tumour that can occur in the lungs with up to 25% of cases being extra pulmonary.
Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Blastoma Pulmonar/genética , Blastoma Pulmonar/patologia , Pré-Escolar , Feminino , HumanosRESUMO
We have studied a total of 36 tumours from 28 patients with germline mutations to the TP53 gene for loss of heterozygosity at TP53 using techniques of both direct sequencing and restriction fragment length polymorphism analysis. All patients were from families conforming to the definition of classical Li-Fraumeni syndrome (LFS) or were Li-Fraumeni-like (LFL). The data we have obtained show that loss of the wild-type TP53 gene is observed in under half (44%) of all tumours, and that the pattern of LOH at TP53 may be mutation specific. LOH has been observed in premalignant as well as invasive tumours. Two tumours (6%) show loss of the mutant allele and retention of the wild-type. To confirm that TP53 is indeed the target for LOH events on chromosome 17, we have used additional microsatellite repeats to examine patterns of allelic imbalance along the length of chromosome 17. Data from this analysis indicate that TP53 is the target of loss, but reveal some other interesting patterns of allelic imbalance at other loci on chromosome 17.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 17 , Genes p53 , Síndrome de Li-Fraumeni/genética , Mutação , Neoplasias/genética , HumanosRESUMO
We report details of a family with classic Li-Fraumeni syndrome in which there is a mutation in codon 344 of the tumour suppressor gene TP53. Codon 344 is a key residue within the tetramerisation domain, and the amino acid substitution of a proline for a leucine is predicted to have profound implications for tetramerisation and potentially DNA binding. This is the first report of a mutation at this residue in either sporadic tumours or in the germline and the first report of a germline mutation within the tetramerisation domain. The family does not appear to be remarkable in the spectrum of tumours, and there is loss of the wild-type allele in a leiomyosarcoma from the proband. A cell line has been established from the tumour of the proband and cytogenetic and molecular studies carried out, providing an extensive analysis in this family.
Assuntos
Códon/genética , Genes p53/genética , Síndrome de Li-Fraumeni/genética , Mutação Puntual/genética , Adulto , Alelos , Sequência de Bases , Feminino , Genótipo , Humanos , Cariotipagem , Masculino , Dados de Sequência Molecular , Linhagem , Análise de Sequência de DNARESUMO
A patient with Beckwith-Wiedemann syndrome (BWS) presented with Wilms' tumour. Examination of the nephrectomy specimen showed, in addition to the tumour, the presence of nephrogenic rests. Nephrogenic rests are thought to be precursor lesions from which a Wilms' tumour may develop. A molecular analysis examining the loss of constitutional heterozygosity (LOCH), initially for chromosome 11, was performed on peripheral blood, the normal kidney, nephrogenic rest and tumour material. The study was extended to include markers from all 23 chromosomes. At each informative, locus, LOCH of the maternal allele was shown in the nephrogenic rest and tumour material. In addition, the normal kidney displayed allele imbalance. It would appear from these results that either extensive LOCH across the genome was an early genetic event in the development of malignancy in this patient or that the tumour and rest developed from cells containing no maternal chromosomes. The apparent LOCH seen in the normal kidney sample implies that full reduction to homozygosity is consistent with a histologically normal appearance. Putative mechanisms to explain this phenomenon are discussed.