RESUMO
Acute lymphoblastic leukemia is the commonest form of cancer in children and adolescents worldwide, and asparaginase is an essential component of successful chemotherapy for this disease associated with long-term survival rates often exceeding 90% in high-income countries. Demonstrably defective preparations of asparaginase, distributed from China and India, increase the burden of morbidity and mortality, reducing attainable survival rates. This adverse outcome is enabled by inadequate regulation and oversight, especially in resource-poor settings in low- and middle-income countries where the great majority of children and adolescents with cancer live. The pediatric oncology community must rise to the challenge.
Assuntos
Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Criança , Humanos , Asparaginase/efeitos adversos , Antineoplásicos/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Taxa de Sobrevida , OncologiaRESUMO
BACKGROUND: It is believed that gonadal and extragonadal germ cell tumors (GCTs) arise from primordial germ cells and may have similar etiopathogenesis. Unlike testicular GCTs, there has been limited comprehensive population-based analysis of ovarian and extragonadal GCTs. METHODS: All malignant GCTs and all central nervous system (CNS) GCTs with benign and uncertain behavior that were registered in England in the age group 0 to 84 years from 1979 to 2003 were included in the current study. Incidence rates were calculated and adjusted to the world standard population. RESULTS: There were 33,364 GCTs (92.5% testes, 3.9% ovary, 3.2% extragonadal) in individuals aged 0 to 84 years. The CNS was the most common extragonadal site. An initial peak in incidence at ages 0 to 4 years of nongerminomas was observed at all sites except ovary. Second incidence peaks between ages 10 to 39 years that were more marked among males also were observed at all sites. The ages at these incidence peaks varied by site and were 10 to 14 years (CNS), 15 to 19 years (ovary), 25 to 29 years (other extragonadal sites), and 30 to 34 years (testes). A statistically significant increase in incidence over time was observed in germinomas (testes, CNS) and nongerminomas (testes, ovary). CONCLUSIONS: The age-incidence patterns observed suggested a common initiation of GCTs in embryonic/fetal life with variable rates of tumor progression as a result of subsequent events that may be site specific. The authors concluded that future genetic studies should consider GCTs from all sites to enable a better understanding of their etiology.
Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias Testiculares/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Inglaterra , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: There has been a steady increase in published research from Europe and North America on the epidemiology of cancers in young people. There are limited data from the developing world. We contrast the incidence of cancer at ages 15-29 years in India and England. PROCEDURE: Malignant neoplasms in those aged 15-29 years registered during 2001-2003 in five urban population-based cancer registries (PBCRs) of India and in eight PBCRs in England were included. Site-based classification was used. Age-standardized incidence rates were expressed per 100,000 person years. RESULTS: In India, 4,864 (5.8%) of 84,450 cases and in England, 8,137 (1.2%) of 65,6752 cancer cases occurred in those aged 15-29 years. For this age group, the incidence rate for males and females in India were 12.91 and 14.19, and in England were 27.75 and 28.88, respectively. In males aged 15-29 years, the three most common cancers in India were leukemia, lymphoma, and central nervous system tumors and in England were cancers of male genital organs, lymphoma, and leukemia. Cancers of female genital organs, breast, and leukemia were most common in females in India and cancers of female genital organs, lymphoma, and melanoma in England. For cancers of mouth, stomach, and gall bladder, the incidence was higher in India. CONCLUSION: Incidence of cancer at ages 15-29 years in England is higher at most sites than in India. Variation in environmental exposures between the two countries might be an explanation. Under-ascertainment of cases and gender bias in seeking healthcare may also influence reported incidence rates in India.
Assuntos
Neoplasias/epidemiologia , Neoplasias/mortalidade , Adolescente , Adulto , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Índia/epidemiologia , Masculino , Prognóstico , Sistema de Registros , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
Bone tumours comprise 0.2% of cancers overall but 5.7% in 15-24 year olds. To explore the relationship with adolescence we have analysed age-incidence patterns of bone tumours in a large national dataset. Data on incident cases of bone tumours in 0-84 year olds in England, 1979-2003, were extracted from national cancer registration data. Incidence rates per million person-years by 5-year age-group, sex, morphology and primary site were calculated and adjusted to the world standard population. Nine thousand one hundred forty-six cases were identified giving an overall age-standardized rate of 7.19 per million person-years. The distribution by morphology was: osteosarcoma, 34.2%; chondrosarcoma, 27.2%; Ewing sarcoma, 19.3%; other, 19.4%. The distribution varied by age. Ewing sarcoma was most common in 0-9 year olds, osteosarcoma in 10-29 year olds and chondrosarcoma in 30-84 year olds. 29.2% of all tumours occurred in 0-24 year olds. Highest incidence of osteosarcoma and Ewing sarcoma in females was in 10-14 year olds. In males, peak incidence occurred at 15-19 years and exceeded that in females. Chondrosarcoma incidence steadily increased with age. The proportions of Ewing sarcomas occurring in respective bones were consistent with those of the adult skeleton by weight. In osteosarcoma tumours of long bones of lower limb were markedly over-represented in the adolescent peak, being six times more than at any other site. Variation in incidence patterns with age and site suggests pubertal bone growth to be a key factor in osteosarcoma while different biological pathways could be relevant for Ewing sarcoma.
Assuntos
Neoplasias Ósseas/epidemiologia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto JovemRESUMO
Despite some reported limitations, Web of Science has been the standard source to assess the impact of individual articles, and consequently journals. By analysing the citations to articles published in the field of paediatric oncology, we demonstrate that Scopus and Google Scholar, the two new citation databases, retrieve more citations than Web of Science. The strength of Scopus lies in identifying non-English literature from Western and Eastern Europe, while Google Scholar is proficient at identifying English and non-English literature from Africa, Asia and Central and South America. These findings have implications for researchers, journals and health libraries.
Assuntos
Bases de Dados Bibliográficas , Fator de Impacto de Revistas , Oncologia , Pediatria , Publicações , Humanos , Idioma , Publicações Periódicas como AssuntoRESUMO
Adhering to treatment can be a significant issue for many patients diagnosed with chronic health conditions and this has been reported to be greater during the adolescent years. However, little is known about treatment adherence in teenage and young adult (TYA) patients with cancer. To increase awareness of the adherence challenges faced by these patients, we have reviewed the published work. The available evidence suggests that a substantial proportion of TYA patients with cancer do have difficulties, with reports that up to 63% of patients do not adhere to their treatment regimens. However, with inconsistent findings across studies, the true extent of non-adherence for these young patients is still unclear. Furthermore, it is apparent that there are many components of the cancer treatment regimen that have yet to be assessed in relation to patient adherence. Factors that have been shown to affect treatment adherence in TYA patients include patient emotional functioning (depression and self-esteem), patient health beliefs (perceived illness severity and vulnerability), and family environment (parental support and parent-child concordance). Strategies that foster greater patient adherence are also identified. These strategies are multifactorial, targeting not only the patient, but the health professional, family, and treatment regimen. This review highlights the lack of interventional studies addressing treatment adherence in TYA patients with cancer, with only one such intervention being identified: a video game intervention focusing on behavioural issues related to cancer treatment and care. Methodological issues in measuring adherence are addressed and suggestions for improving the design of future adherence studies highlighted, of which there is a great need.
Assuntos
Neoplasias/terapia , Cooperação do Paciente , Adolescente , Adulto , Cultura , Emoções , Família , Humanos , Neoplasias/psicologia , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: High accrual to clinical trials enables new treatment strategies to be tested rapidly, accurately and with generalisability. Ethical standards also must be high so that participation is voluntary and informed. However, this can be difficult to achieve in trials with complex designs and in those which are closely embedded in clinical practice. Optimal recruitment requires a balance of both ethical and accrual considerations. In the context of a trial of stratified treatments for children with acute lymphoblastic leukaemia (UKALL2003) we examined how recruitment looked to an observer and how it felt to the parents, to identify how doctors' communication could promote or inhibit optimal recruitment. METHODS: We audio-recorded, transcribed and analysed routine doctor-patient consultations (n = 20) and interviews between researchers and parents (n = 30 parents) across six UK treatment centres. Analysis was informed by the constant comparative method. For consultation transcripts, analysis focussed on how doctors presented the trial. We compared this with analysis of the interview transcripts which focussed on parents' perceptions and understanding of the trial. RESULTS: Parents and doctors discussed the trial in most consultations, even those that did not involve a decision about randomisation. Doctors used language allying them both with the trial and with the parent, indicating that they were both an 'investigator' and a 'clinician'. They presented the trial both as an empirical study with a scientific imperative and also as offering personalisation of treatment for the child. Parents appeared to understand that trial involvement was voluntary, that it was different from routine care and that they could withdraw from the trial at any time. Some were confused about the significance of the MRD test and the personalisation of treatment. CONCLUSIONS: Doctors communicated in ways that generally promoted optimal recruitment, indicating that trials can be embedded into clinical practice. However, parents were unclear about some details of the trial's rationale, suggesting that recruitment to trials with complicated designs, such as those involving stratified treatments, might need enhanced explanation.
Assuntos
Ensaios Clínicos como Assunto/normas , Pais , Seleção de Pacientes/ética , Pediatria/normas , Relações Profissional-Família , Equipolência Terapêutica , Adulto , Atitude Frente a Saúde , Criança , Ensaios Clínicos como Assunto/ética , Humanos , Entrevistas como Assunto , Leucemia-Linfoma Linfoblástico de Células Precursoras , Reino UnidoRESUMO
Reported increases in the incidence of CNS tumours in the developed world in the 1970s to 1990s have been a cause for concern and debate. It still remains to be adequately answered whether these increases are true or an artefact of changes in diagnostic and registration practices. Using high-quality national cancer registration data, we have analysed incidence trends for each major histological subgroup of CNS tumour (2000 World Health Organisation (WHO) classification) registered in those aged 0-84 years for the whole of England during the period 1979 through 2003. 134,509 primary CNS tumours of malignant, benign and uncertain behaviour located in the brain, meninges, spinal cord, cranial nerves, other parts of the central nervous system and in the pituitary and pineal glands were registered. In summary, we present the single largest nationwide study on the longitudinal incidence trends of CNS tumours. The increase in incidence observed in the 1970s and 1980s was mainly in the young and the elderly and has now plateaued and may even be decreasing. There is however variation in trends by histology. The incidence of some histological sub-groups has continued to increase until the most recent period of analysis. Much of the initial increase can be attributed to the emergence of much more widely available neuroimaging, while the most recent incidence changes for specific sub-groups of CNS tumours appear to be due to greater diagnostic specificity leading to a shift in registered categories. However, the trends for high-grade astrocytomas and other gliomas need further observation and investigation.
Assuntos
Neoplasias do Sistema Nervoso Central/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Lactente , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sistema de RegistrosRESUMO
Although the epidemiology of malignant bone tumours in children and young adults has been explored, no definitive causation of any specific tumour has yet been identified. We performed a literature review (1970-2008) to find all papers covering possible aetiological factors involved in the development of bone tumours in children and young adults. Several associations have been reported with some consistency: the presence of hernias and Ewing sarcoma; high fluoride exposure and osteosarcoma; and parental farming and residence on a farm, younger age at puberty and family history of cancer for all bone tumours, especially osteosarcoma. Clearly further research is needed to confirm or refute these putative risk factors. It is likely that studies of gene-environment interactions may prove to be the most fruitful of future research.
Assuntos
Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/economia , Criança , Humanos , Seguro Saúde/tendências , Sobreviventes , Adulto JovemRESUMO
l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
Assuntos
Antineoplásicos/metabolismo , Asparaginase/metabolismo , Catepsina B/fisiologia , Cisteína Endopeptidases/fisiologia , Linfócitos/enzimologia , Lisossomos/enzimologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Asparaginase/uso terapêutico , Linhagem Celular , HumanosRESUMO
OBJECTIVES: Non-adherence (NA) by adolescents receiving cancer treatment is believed to be a major problem. However, adequate measures of NA have not been developed. The purpose of this study was to (1) assess the internal reliability of a new scale reflecting low-risk NA behaviours, (2) examine whether the scores on this scale were associated with high-risk NA behaviours and (3) assess the relationship between NA behaviours and patient attitudes towards stopping treatment. METHODS: Thirty-three patients (16-24 years) with solid tumours reported on their previous adherence with treatment. Low-risk NA behaviours were assessed on a 0-40 scale derived from the sum of 10 items. High-risk NA behaviours and attitudes towards stopping treatment were assessed by questions with yes/no response options. RESULTS: Internal reliability of the low-risk NA scale was alpha=0.73. Patients not seeking help for pyrexia had higher total low-risk NA scores than those who sought help (mean 7.4, SD 5.3 vs mean 3.5, SD 3.6, t=2.1, p=0.03). There was also a trend for individuals who ignored pyrexia to be more likely to have contemplated stopping treatment than those who sought medical assistance (Fisher's Exact=0.09). CONCLUSIONS: A scale reflecting low-risk NA behaviour had good internal reliability and was associated with not seeking help when pyrexic. Ignoring a temperature was also associated with contemplating stopping treatment. We are now conducting a prospective study using the measure to assess validity against a range of information regarding NA.
Assuntos
Neoplasias/psicologia , Neoplasias/terapia , Cooperação do Paciente/psicologia , Papel do Doente , Inquéritos e Questionários , Adolescente , Diarreia/psicologia , Feminino , Febre de Causa Desconhecida/psicologia , Hemorragia/psicologia , Humanos , Masculino , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Pacientes Desistentes do Tratamento/psicologia , Psicometria/estatística & dados numéricos , Reprodutibilidade dos Testes , Assunção de Riscos , Adulto JovemRESUMO
Around 25% of all tumors in those 0-14 years of age and 9% in those 15-24 years of age involve the CNS. They are the most common cause of cancer-related deaths in both age groups. In adults 25-84 years of age, the proportion of CNS tumors is 2%; 5-year overall survival is 10%-15%; and survivors have considerable morbidity. Comprehensive up-to-date population-based incidence data on these tumors are lacking. We present incidence rates for primary CNS tumors based on data derived from the high-quality national cancer registration system in England. A total of 54,336 CNS tumors of malignant, benign, and uncertain behavior were registered across the whole of England from 1995 through 2003. The age-standardized rates for all ages (0-84 years) was 9.21 per 100,000 person-years. This is higher than previously reported for England because it includes nonmalignant CNS tumors and hence gives a more accurate picture of burden of disease. The age-standardized rates for those 0-14 years of age, 15-24 years of age, and 25-84 years of age were 3.56, 3.26, and 14.57 per 100,000 person-years, respectively. In this article, we describe the changing patterns in the epidemiology of primary CNS tumors in these three age groups with respect to sex, tumor behavior, and histology using the current WHO classification. This information will provide a reference for future studies nationally and internationally and make comparisons relevant and meaningful.
Assuntos
Neoplasias Encefálicas/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Cancer for teenagers and young adults represents a major source of morbidity and mortality. Trends in cancer incidence can provide pointers concerning how changes in the environment and in personal behavior affect cancer risks. METHODS: Data on 39,129 neoplasms in individuals ages 13 to 24 years who were diagnosed in England from 1979 to 2003 were analyzed. Variability in incidence by time period and differences in the time trends by age group, sex, and geographic region were analyzed using generalized linear models. RESULTS: Incidence rates of leukemias, lymphomas, central nervous system, bone, and germ cell tumors; melanoma; and carcinomas of the thyroid, ovary, cervix, and colon/rectum increased over time (all P < .01); whereas the incidence of carcinomas of the stomach and bladder decreased (both P < .01). These changes were consistent by age, sex, and region for most neoplasms. Melanoma incidence stabilized in southern England by 1993 but continued to increase in northern England (P = .001). The increase in non-Hodgkin lymphoma was greater in individuals ages 20 to 24 year than in younger individuals, but the increase in Hodgkin lymphoma was confined to individuals ages 13 to 14 years. CONCLUSIONS: The changes in incidence rates may have been caused in part by environmental changes and in part by behavioral changes in young individuals. Some of these results can be used to inform public health campaigns, which can be constructed to encourage better lifestyle choices by young individuals.
Assuntos
Neoplasias/epidemiologia , Adolescente , Distribuição por Idade , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Masculino , Adulto JovemRESUMO
A role for genetic susceptibility in the aetiology of childhood lymphomas was investigated in 454 families of children with histologically confirmed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) from Northwest England. Cancers in parents were obtained from the UK National Health Service Central Register and in other close relatives by interview with the parents. The cancer incidence among relatives was compared with expected incidence based on cancer registry data for England. There were 197 cancers in relatives (SIR 1.0 95% CI 0.8-1.1). In families of children with HL, there was an excess of HL in the first degree relatives (SIR 5.8 95% CI 1.2-16.9). Excesses of HL diagnosed under population median age (SIR 4.1 95% CI 1.1-10.6) were seen among all relatives and relatives of children who were below the median age at diagnosis (SIR 5.5 95% CI 1.1-16.0). In families of children with NHL, there were non-significant excesses of central nervous system (CNS) tumours in the first degree relatives (SIR 2.9 95% CI 0.8-7.4) and in the second and third degree relatives (SIR 1.5). There were significant excesses of CNS tumours diagnosed under the population median age (SIR 2.8 95% CI 1.1-5.8) in all relatives. Excess CNS tumours were also seen among relatives of children below the median age at diagnosis (SIR 3.2 95% CI 1.1-7.6). In conclusion, genetic susceptibility in some families of children with lymphoma might be operating, but aetiologies in HL and NHL appear to be different. Possible interpretations of our findings, in the context of putative genetic and infectious aetiologies, are discussed.
Assuntos
Predisposição Genética para Doença , Doença de Hodgkin/genética , Linfoma não Hodgkin/genética , Neoplasias/epidemiologia , Criança , Feminino , Humanos , Incidência , Masculino , Linhagem , Sistema de Registros , Fatores de RiscoRESUMO
We investigated the relationship between childhood leukaemia and preceding history of allergy. A nationwide case-control study of childhood cancers was conducted in the United Kingdom with population-based sampling of cases (n = 839) and controls (n = 1,337), matched on age, sex and region of residence. Information about clinically diagnosed allergies was obtained from primary care records. More than a third of subjects had at least one allergy diagnosed prior to leukaemia diagnosis (cases) or pseudo-diagnosis (controls). For both total acute lymphoblastic leukaemia (ALL) and common-ALL/precursor B-cell ALL (c-ALL), a history of eczema was associated with a 30% significant reduction in risk: the odds ratios (OR) and 95% confidence intervals (CI) were 0.70 (0.51-0.97) and 0.68 (0.48-0.98), respectively. Similar associations were observed for hayfever (OR = 0.47; 95% CI: 0.26-0.85 and OR = 0.62; 95% CI: 0.33-1.16 for ALL and c-ALL, respectively). No such patterns were seen either for asthma and ALL, or for any allergy and acute myeloid leukaemia. A comparative analysis of primary care records with parents recall of allergy revealed only moderate agreement with contemporaneous clinical diagnoses for both cases and controls--confirming the unreliability of parental report at interview. Our finding of a reciprocal relationship between allergy and ALL in children is compatible with the hypothesis that a dysregulated immune response is a critical determinant of childhood ALL.
Assuntos
Hipersensibilidade/epidemiologia , Leucemia/epidemiologia , Adolescente , Asma/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Eczema/epidemiologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Prontuários Médicos , Rinite Alérgica Sazonal/epidemiologia , Fatores de RiscoRESUMO
Patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21) comprise a novel and distinct biological subgroup. We prospectively screened 1630 (84%) patients treated on the UK MRC ALL97 protocol for iAMP21 and herein present demographic, clinical, and survival data on the 28 (2%) children found to harbor this abnormality. They had a common or pre-B ALL immunophenotype, were significantly older (median 9 years vs 5 years), and had a lower white cell count (median 3.9 vs 12.4) compared with children without this abnormality. Notably, patients with iAMP21 had a significantly inferior event-free and overall survival at 5 years compared with other patients: 29% (95% confidence interval [CI], 13%-48%) versus 78% (95% CI, 76%-80%) and 71% (95% CI, 51%-84%) versus 87% (95% CI, 85%-88%), respectively. As a result of this 3-fold increase in relapse risk, newly diagnosed patients with iAMP21 recruited to the current UK MRC ALL2003 trial are being treated on the high-risk arm and are considered for bone marrow transplantation in first remission.
Assuntos
Cromossomos Humanos Par 21/genética , Amplificação de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Criança , Pré-Escolar , Citogenética , Feminino , Humanos , Lactente , Masculino , Prognóstico , Taxa de SobrevidaAssuntos
Influenza Humana/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Linfoma de Burkitt/epidemiologia , Criança , Surtos de Doenças , Humanos , Incidência , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Reino Unido/epidemiologiaRESUMO
Childhood acute myeloid leukaemia (AML) is uncommon. Children with Fanconi anaemia (FA), however, have a very high risk of developing AML. FA is a rare inherited disease caused by mutations in at least 12 genes, of which Fanconi anaemia group G gene (FANCG) is one of the commonest. To address to what extent FANCG variants contribute to sporadic childhood AML, we determined the spectrum of FANCG sequence variants in 107 children diagnosed with sporadic AML, using polymerase chain reaction (PCR), fluorescent single-strand conformational polymorphism (SSCP) and sequencing methodologies. The significance of variants was determined by frequency analysis and assessment of evolutionary conservation. Seven children (6.5%) carried variants in FANCG. Two of these carried two variants, including the known IVS2 + 1G>A mutation with the novel missense mutation S588F, and R513Q with the intronic deletion IVS12-38 (-28)_del11, implying that these patients might have been undiagnosed FA patients. R513Q, which affects a semi-conserved amino acid, was carried in two additional children with AML. Although not significant, the frequency of R513Q was higher in children with AML than unselected cord bloods. While FANCG mutation carrier status does not predispose to sporadic AML, the identification of unrecognised FA patients implies that FA presenting with primary AML in childhood is more common than suspected.
Assuntos
Proteína do Grupo de Complementação G da Anemia de Fanconi/genética , Anemia de Fanconi/complicações , Leucemia Mieloide/genética , Mutação , Doença Aguda , Adolescente , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , DNA de Neoplasias/genética , Anemia de Fanconi/genética , Feminino , Humanos , Lactente , Leucemia Mieloide/etiologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase/métodos , Polimorfismo Conformacional de Fita Simples , Alinhamento de SequênciaRESUMO
Epidemiological evidence suggests that infection is involved in the etiology of common acute lymphoblastic leukemia, either by stimulating an inappropriate immune response or in the form of a classical transforming agent. In an attempt to elucidate the role that infection is playing in this disease, we used representational difference analysis (RDA) to examine tumor samples for the presence of exogenous genomes. Twenty RDA experiments were carried out, using four different restriction enzymes, but no exogenous sequences were identified within leukemic cells. These results suggest that it is unlikely that a single, direct transforming agent is involved in the pathogenesis of common acute lymphoblastic leukemia.
Assuntos
Transformação Celular Viral , Leucemia-Linfoma Linfoblástico de Células Precursoras/virologia , Adolescente , Criança , Pré-Escolar , DNA de Neoplasias/análise , Genoma Viral , Genômica , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologiaRESUMO
We previously demonstrated significant space-time clustering amongst cases of childhood leukaemia (in particular acute lymphoblastic leukaemia (ALL)), central nervous system (CNS) tumour (especially astrocytoma), soft tissue sarcoma and Wilms' tumour. We hypothesised that there may be common aetiological mechanisms between some of these diagnostic groups. To test this hypothesis we analysed for cross-space-time clustering between these diagnostic groups, using population-based data from north-west England. Data were examined by a second-order procedure based on K-functions. Reference points in time and space were dates and addresses at birth and diagnosis. The results showed statistically significant (P < 0.05) cross-clustering between cases of leukaemia and CNS tumour and between cases of ALL and astrocytoma. There was no statistically significant cross-clustering of Wilms' tumours and soft tissue sarcomas with any other malignancy. In conclusion, these findings are consistent with common, possibly infectious, aetiological mechanisms for childhood leukaemia (particularly ALL) and CNS tumours (particularly astrocytoma).