RESUMEN
There have been few studies addressing uptake of predictive testing for BRCA1/2, only one comparing a proactive with usual family networking approach to dissemination. We report uptake of predictive genetic testing after directly offering BRCA1 presymptomatic genetic testing to 100 individuals in two generations of 5 large BRCA1 families compared with service testing of 196 families since that time. Uptake was significantly higher in the first generation (group 1), who were directly offered testing, and much higher in females. Seventy-four percent of unaffected women in the first generation proceeded to testing, 42% of men. This decreased to 44% of women in the second generation (group 2) and 9% males (p = 0.0003). Uptake in unaffected individuals in the final group (group 3) with no proactive approach was significantly lower than that in the first group. Overall uptake after 10 years was 56% (95% confidence interval, CI, 50-62%) for group 1 and 36% (95% CI 34.3-37.7%) for 1084 group 3 individuals (p = 0.0003). Among women, uptake was 74% (95% CI 67-81%) in group 1 at 10 years compared with 51.5% (95% CI 49-54%) in 552 group 3 women (p = 0.023). In men, uptake was 42% (95% CI 33-52%) in group 1 and 21.1% (95% CI 18.1-23.1%) among 532 men in group 3 (p = 0.0098). Although these results are not from a randomized trial, they show particularly among men a substantially higher uptake of genetic services with a direct approach. Importance should be given to more proactive approaches to ensure that men in BRCA1/2-positive families receive the appropriate information.
Asunto(s)
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/psicología , Pruebas Genéticas/psicología , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Reguladoras de la Apoptosis , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Neoplasias de la Mama/genética , Familia/psicología , Femenino , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las PruebasRESUMEN
Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1.
Asunto(s)
Alelos , Antígenos HLA-DQ/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Secuencia de Bases , Niño , Cadenas beta de HLA-DQ , Humanos , Recién Nacido , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-Simple , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
It has been suggested that childhood leukaemia may be the abnormal outcome of a common infection. Rare events caused by common environmental events such as infections are likely to be influenced by host genetic susceptibility. We have therefore investigated whether immunogenetic susceptibility contributes to the risk of childhood common ALL (c-ALL). In this preliminary study, we report that children with c-ALL (n = 63) carry the HLA-DPB1 locus allele *0201 twice and nearly three times more frequently than adult (n = 92; relative risk (RR) = 2.9, P < 0.05) or infant controls (n = 82; RR = 2.1). Moreover, children with c-ALL are 3-4 times more likely than controls to be heterozygous for DPB1*0201/*0301, /*0401 and /*0402 (RRadult controls = 3.9; RRinfant controls = 2.8). These results suggest that HLA-DPB1*0201 either alone or with other DPB1 alleles contributes to the risk of childhood c-ALL, possibly by increasing susceptibility to an infectious agent.
Asunto(s)
Antígenos HLA-DP/genética , Infecciones/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/etiología , Adolescente , Alelos , Niño , Preescolar , Susceptibilidad a Enfermedades/inmunología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA-DP/análisis , Cadenas beta de HLA-DP , Humanos , Lactante , Infecciones/inmunología , Masculino , Reacción en Cadena de la Polimerasa , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunologíaRESUMEN
The entire coding sequence of the p53 gene was analysed for the presence of mutations in 12 families conforming to a restricted definition of Li-Fraumeni syndrome (classic LFS) and nine families with features of LFS conforming to a broader definition. Mutations were detected in seven families. Six were point mutations with one each affecting codons 175, 180, and 220 and three affecting codon 248. The seventh was a deletion/insertion mutation in exon 4. Germline mutations in p53 were a feature of families which included children with rhabdomyosarcoma and/or adrenal cortical carcinoma. Germline p53 mutations were detected in six of the nine families with such tumors. An analysis of these 7 mutations, together with 34 published examples, showed that more than one-half were transitions at CpG dinucleotides, suggesting that the majority of germline p53 mutations may arise as a result of spontaneous events. The most common cancers occurring in the 41 families with germline p53 mutations, in common with classic LFS, were bone and soft tissue sarcoma, breast cancer, brain tumors, leukemia, and adrenocortical carcinoma, although less than one-half of the probands with germline p53 mutations came from classic LFS families. More than one-half of the cancers overall and nearly one-third of the breast cancers were diagnosed before 30 years of age. These observations have important implications for asymptomatic carriers of germline p53 mutations, and there is a need for international collaboration in the development of protocols for the management of such families.