RESUMEN
OBJECTIVE: Glucocerebrosidase (GBA) gene mutations represent a strong risk factor for Parkinson disease (PD). PD penetrance in GBA mutation carriers, which represents a key issue for genetic counseling, especially for relatives of patients with Gaucher disease (GD), is unknown. Our objective was to estimate PD penetrance in a familial study of GBA mutation carriers. METHODS: Probands with familial PD were recruited through the French Parkinson Disease Genetic Study Group. All GBA exons were sequenced in probands and their relatives. To estimate the age-specific cumulative PD risk (i.e., penetrance) in GBA mutation carriers, we used the proband's phenotype exclusion likelihood method and corrected for selection of familial cases by considering the status of one affected relative per family as unknown. RESULTS: Of 525 probands with familial PD, 24 (4.6%) were GBA mutation carriers. Of their 256 relatives, 43 (16.8%) had PD and 26 of 32 affected relatives tested for GBA mutations were mutation carriers; 213 relatives did not have PD and 31 of 71 of unaffected relatives tested for GBA mutations were mutation carriers. Under a dominant model, penetrance was estimated as 7.6%, 13.7%, 21.4%, and 29.7% at 50, 60, 70, and 80 years, respectively. There was no significant difference in penetrance at 70 years between N370S carriers, L444P carriers, and carriers of rarer mutations. CONCLUSION: The relatively high penetrance estimate in GBA carriers obtained in this study should lead to consideration of GBA as a dominant causal gene with reduced penetrance and should be taken into account for genetic counseling in relatives of patients with GD and patients with GBA-associated PD.
Asunto(s)
Glucosilceramidasa/genética , Enfermedad de Parkinson/genética , Adulto , Anciano , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Mutación , Penetrancia , FenotipoRESUMEN
Organised since 1990 in France, cancer genetics has been strengthened since 2003 by the programme "Plan Cancer" which resulted in an improvement of the organisation of activities. The aim of this review is to present an update of the estimation of the needs of the population in this field for the next ten years, provided by a group of experts mandated by the French National Cancer Institute. Identification and management of major hereditary predispositions to cancer have a major impact on decrease in mortality and incidence. Sensitivity of criteria for the detection of BRCA1/2 mutations could be substantially improved by enlarging the indication for genetic testing to isolated cases of ovarian cancer occurring before 70 years and to familial cases occurring after this age limit. In the Lynch syndrome, the present criteria would have an excellent sensitivity for the detection of mutations in the mismatch repair (MMR) genes if the pre-screening of tumours on microsatellite instability (MSI) phenotype was effective, but these criteria are actually poorly applied. However, genetic testing should not be proposed to all the patients affected by tumours belonging to the spectrum of major predispositions and a fortiori to unaffected persons unless an affected relative has been identified as a carrier. The prescription of tests should continue to be strictly controlled and organised, in patients as well as in at-risk relatives. The enlargement of criteria and the improvement in the spreading of recommendations should result in an increase of genetic counselling activity and of the prescriptions of tests by a factor 2 to 4, and to a lesser extent in the clinical management of at risk persons. In a near future, it appears important to mandate experts on specific issues such as the determinants of the lack of effective application of tumour screening for MSI phenotype, the recommendations for the identification and the management of MYH-associated polyposis, or the predictive value of tumour characteristics for the identification of BRCA1/2 mutations. The expected increase in cancer genetics activity will need an optimal organisation to increase the throughput. Such measures will help in facing up to new predispositions that will probably be identified in common cancers.
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Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Necesidades y Demandas de Servicios de Salud , Neoplasias/genética , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Femenino , Predicción , Francia , Genes BRCA1 , Genes BRCA2 , Pruebas Genéticas/psicología , Necesidades y Demandas de Servicios de Salud/organización & administración , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Necesidades y Demandas de Servicios de Salud/tendencias , Humanos , Masculino , Mutación , Neoplasias/diagnóstico , Neoplasias/prevención & control , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & controlRESUMEN
BACKGROUND AND PURPOSE: Familial amyloid polyneuropathy (FAP) type I is a severe autosomal dominant inherited neuropathy associated with mutations in the transthyretin (TTR) gene. Significant phenotypic variability is seen amongst families with distinct geographic origin, especially regarding penetrance and age of onset. The aim of this study was to estimate the penetrance of FAP in Brazilian families. METHODS: Twenty-two distinct families were ascertained through genetically confirmed index cases and included in this study. Genealogical and clinical data were obtained from a total of 623 individuals, including 126 affected by FAP. In 15 families, TTR genotyping was performed in all available relatives (n = 86), after informed written consent. Seven families did not consent for genetic testing, but agreed to provide clinical and genealogical data. Penetrance was estimated using a previously described method based on survival analysis and corrected for ascertainment bias. RESULTS: Mean age of onset in our sample was 34.5 years, with a significant earlier onset in males (31.1 vs. 35.9, P < 0.0001). The penetrance of FAP in our sample was estimated as 83% (95% CI: 66-99) after 60 years. CONCLUSION: Our results provide new information on FAP in Brazilian patients and may be helpful in the genetic counseling of this population.
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Neuropatías Amiloides Familiares/genética , Penetrancia , Prealbúmina/genética , Adulto , Factores de Edad , Edad de Inicio , Anciano , Brasil , Familia , Femenino , Humanos , Funciones de Verosimilitud , Masculino , Persona de Mediana Edad , Mutación Missense , Análisis de Secuencia de ADN , Factores Sexuales , Análisis de Supervivencia , Adulto JovenRESUMEN
In diseases caused by a deleterious gene mutation, knowledge of age-specific cumulative risks is necessary for medical management of mutation carriers. When pedigrees are ascertained through at least one affected individual, ascertainment bias can be corrected by using a parametric method such as the Proband's phenotype Exclusion Likelihood, or PEL, that uses a survival analysis approach based on the Weibull model. This paper proposes a nonparametric method for penetrance function estimation that corrects for ascertainment on at least one affected: the Index Discarding EuclideAn Likelihood or IDEAL. IDEAL is compared with PEL, using family samples simulated from a Weibull distribution and under alternative models. We show that, under Weibull assumption and asymptotic conditions, IDEAL and PEL both provide unbiased risk estimates. However, when the true risk function deviates from a Weibull distribution, we show that the PEL might provide biased estimates while IDEAL remains unbiased.
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Modelos Genéticos , Penetrancia , Estadísticas no Paramétricas , Femenino , Humanos , Funciones de Verosimilitud , Masculino , Modelos Estadísticos , Epidemiología Molecular , Linaje , Fenotipo , Tamaño de la Muestra , Análisis de SupervivenciaRESUMEN
Providing valid risk estimates of a genetic disease with variable age of onset is a major challenge for prevention strategies. When data are obtained from pedigrees ascertained through affected individuals, an adjustment for ascertainment bias is necessary. This article focuses on ascertainment through at least one affected and presents an estimation method based on maximum likelihood, called the Proband's phenotype exclusion likelihood or PEL for estimating age-dependent penetrance using disease status and genotypic information of family members in pedigrees unselected for family history. We studied the properties of the PEL and compared with another method, the prospective likelihood, in terms of bias and efficiency in risk estimate. For that purpose, family samples were simulated under various disease risk models and under various ascertainment patterns. We showed that, whatever the genetic model and the ascertainment scheme, the PEL provided unbiased estimates, whereas the prospective likelihood exhibited some bias in a number of situations. As an illustration, we estimated the disease risk for transthyretin amyloid neuropathy from a French sample and a Portuguese sample and for BRCA1/2 associated breast cancer from a sample ascertained on early-onset breast cancer cases.
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Enfermedades Genéticas Congénitas/genética , Factores de Edad , Neuropatías Amiloides/genética , Sesgo , Neoplasias de la Mama/genética , Francia , Genes BRCA1 , Genes BRCA2 , Humanos , Funciones de Verosimilitud , Modelos Genéticos , Modelos Estadísticos , Linaje , Fenotipo , Portugal , Prealbúmina/genética , RiesgoRESUMEN
We have performed an extensive analysis of TP53 in 474 French families suggestive of Li-Fraumeni syndrome (LFS), including 232 families fulfilling the Chompret criteria. We identified a germline alteration of TP53 in 82 families (17%), in 67/232 of the families fulfilling the Chompret criteria (29%) and in 15/242 which did not fulfil these criteria (6%). Most of the alterations corresponded to missense mutations (67%), and we identified in four families genomic deletions removing the entire TP53 locus, the promoter and the non-coding exon 1, or exons 2-10. These results represent a definitive argument demonstrating that LFS results from TP53 haplodeficiency. The mean ages of tumour onset were significantly different between patients harbouring TP53 missense mutations and other types of alterations, missense mutations being associated with a 9 year earlier tumour onset. These results confirm that missense mutations not only inactivate p53 but also have an additional oncogenic effect. Germline alterations of TP53 that lead exclusively to loss of function are therefore associated with a later age of tumour onset and the presence of such mutations should be considered in atypical LFS families with tumours diagnosed after 40 years.
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Genes p53 , Predisposición Genética a la Enfermedad , Síndrome de Li-Fraumeni/genética , Femenino , Francia , Eliminación de Gen , Humanos , Masculino , Mutación Missense , Neoplasias/genética , LinajeRESUMEN
We have previously shown that patients with renal fibromuscular dysplasia (FMD) have asymptomatic carotid lesions and that familial forms may occur. The objective of this study was to test whether carotid lesions could be detected in relatives of familial cases. High-resolution echotracking of the carotid artery was performed in 47 relatives of 13 cases from six families. This non-invasive investigation led to a semiquantitative arterial score that was compared with that obtained for 47 controls matched for age and sex and that for 125 sporadic cases. Familial resemblance was tested by using a generalized estimating equation approach taking into account the clustering of scores in families. As expected, FMD cases had a significantly higher score than controls (4.02 vs 2.52, P<10(-5)). Familial cases were not significantly different from sporadic cases. Of interest, the 47 apparently healthy relatives of familial cases had also a high carotid score (4.17), very significantly higher than that of controls (2.52, P<10(-5)) even though lower than the corresponding index FMD cases (4.81, P=0.01). Segregation analysis showed that 52% of the descendants of subjects with a score >4 had a score >4, a proportion consistent with autosomal-dominant transmission of the trait. Altogether these results strengthen the hypothesis of renal FMD being a systemic arterial disease and argue for a familial resemblance that may be due to a major genetic effect. The carotid score obtained by high-resolution echotracking may provide a non-invasive surrogate marker for renal FMD of potential value for use in linkage strategies on large pedigrees.
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Enfermedades de las Arterias Carótidas/genética , Arteria Carótida Común/patología , Displasia Fibromuscular/genética , Obstrucción de la Arteria Renal/genética , Adulto , Anciano , Análisis de Varianza , Enfermedades de las Arterias Carótidas/complicaciones , Estudios de Casos y Controles , Análisis por Conglomerados , Femenino , Displasia Fibromuscular/complicaciones , Francia , Predisposición Genética a la Enfermedad , Humanos , Hipertensión/etiología , Hipertensión/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Curva ROC , Análisis de Regresión , Obstrucción de la Arteria Renal/complicaciones , Proyectos de Investigación , Análisis de Supervivencia , Túnica Íntima/patología , Túnica Media/patologíaRESUMEN
BACKGROUND: Little is known about compliance with colonoscopy as a screening method in first-degree relatives of patients with large adenomas. Aims To evaluate the compliance with screening colonoscopy among this population, and its determinants. METHODS: Data were obtained from the family part of the GEADE study, a study on genetic factors of colorectal adenomas. Index cases were 306 patients with adenomas > or = 10 mm. All living first-degree relatives aged 40-75 who could be contacted by the index case were asked to undergo a colonoscopy, unless they had had one in the previous 5 years. RESULTS: Among 674 eligible relatives, 56 had had a colonoscopy within the preceding 5 years and 114 underwent a screening colonoscopy resulting in a compliance with screening colonoscopy of 18%. This was not related to most characteristics of index cases. Compliance was significantly lower when the index case lived in the Greater Paris area than when he/she lived in other areas (12% vs. 21%). It was higher in siblings (18%) and offspring (23%) than in parents (9%) and in relatives under 55 years old (22%) than in relatives aged 55 and over (15%). CONCLUSIONS: Compliance with colonoscopy was low in first-degree relatives of patients with large adenomas. The reasons for this should be determined and appropriate strategies developed to increase compliance.
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Adenoma/diagnóstico , Colonoscopía/estadística & datos numéricos , Neoplasias Colorrectales/diagnóstico , Cooperación del Paciente/estadística & datos numéricos , Adenoma/genética , Adulto , Anciano , Neoplasias Colorrectales/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
BACKGROUND: The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. METHODS: Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. MAIN RECOMMENDATIONS: The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.
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Adenocarcinoma/genética , Neoplasias del Colon/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Endometriales/genética , Neoplasias del Recto/genética , Susceptibilidad a Enfermedades , Femenino , Francia , Humanos , MutaciónRESUMEN
Li-Fraumeni syndrome, resulting from p53 (TP53) germline mutations, represents one of the most devastating genetic predispositions to cancer. Recently, the MDM2 SNP309 (T-->G variation) was shown to be associated with accelerated tumour formation in p53 mutation carriers. The impact of the common p53 codon 72 polymorphism on cancer risk remains controversial. We therefore investigated the effect of these two polymorphisms in 61 French carriers of the p53 germline mutation. The mean age of tumour onset in MDMD2 SNP309 G allele carriers (19.6 years) was significantly different from that observed in patients homozygous for the T allele (29.9 years, p<0.05). For the p53 codon 72 polymorphism, the mean age of tumour onset in Arg allele carriers (21.8 years) was also different from that of Pro/Pro patients (34.4 years, p<0.05). We observed a cumulative effect of both polymorphisms because the mean ages of tumour onset in carriers of the MDM2G and p53Arg alleles (16.9 years) and those with the MDM2T/T and p53Pro/Pro genotypes (43 years) were clearly different (p<0.02). Therefore, our results confirm the impact of the MDM2 SNP309 G allele on the age of tumour onset in germline p53 mutation carriers, and suggest that this effect may be amplified by the p53 72Arg allele. Polymorphisms affecting p53 degradation therefore represent one of the rare examples of modifier genetic factors identified to date in mendelian predispositions to cancer.
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Genes p53 , Predisposición Genética a la Enfermedad , Síndrome de Li-Fraumeni/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-mdm2/genética , Adolescente , Adulto , Edad de Inicio , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Mutación de Línea Germinal , Heterocigoto , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/epidemiología , Masculino , Persona de Mediana Edad , Factores de RiesgoAsunto(s)
Neuropatías Amiloides/genética , Tamización de Portadores Genéticos , Mutación , Prealbúmina/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides/epidemiología , Femenino , Francia/epidemiología , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Penetrancia , Portugal/epidemiología , Razón de MasculinidadAsunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Sesgo , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Femenino , Tamización de Portadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/epidemiología , Neoplasias/genética , LinajeRESUMEN
Cleft lip with or without cleft palate (CL/P) is one of the most common congenital malformations in humans occurring with a birth prevalence of approximately 1:1,000. CL/P may be part of a defined syndrome, sequence or association, although most individual or familial cases present as an isolated (nonsyndromic) malformation (NSCL/P). Inheritance is generally regarded as multigenic although, in some families, NSCL/P seemingly segregates as a monogenic trait. On the other hand, van der Woude syndrome (vWS) is a rare autosomal dominant with cardinal features of lower-lip pits (LLP) and CL/P or cleft palate (alone). Since none of these traits is present in all mutation carriers, some individual or familial vWS cases, especially those lacking LLP, are indiscernible from NSCL/P, raising the question whether allelic variation at the vWS locus could underlie NSCL/P. This question was addressed using parametric linkage (LOD score) analysis in 21 multiplex NSCL/P families based on a tightly linked microsatellite marker (D1S3753), and nonparametric analysis using the transmission/disequilibrium test (GTDT) in 106 NSCL/P triads and selecting markers D1S205, D1S491, and D1S3753. No evidence for linkage of NSCL/P to vWS was found on the 21 families using the LOD score approach. In contrast, TDT yielded a significant P value of 0.04 for D1S205, supporting involvement of vWS in NSCL/P in a complex, modifying/polygenic manner rather than as a monogenic/major disease locus.
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Labio Leporino/genética , Fisura del Paladar/genética , Alelos , Femenino , Genotipo , Heterocigoto , Humanos , Anomalías Maxilomandibulares , Desequilibrio de Ligamiento/genética , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , LinajeRESUMEN
The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.
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Genes p53/genética , Síndrome de Li-Fraumeni/genética , Proteínas Serina-Treonina Quinasas , Adulto , Factores de Edad , Quinasa de Punto de Control 2 , Niño , Femenino , Silenciador del Gen , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Humanos , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/terapia , Masculino , Mamografía , Mutación , Fosforilación , Guías de Práctica Clínica como Asunto , Proteínas Quinasas/genéticaRESUMEN
Although a few familial forms of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD) have been reported, this disorder is usually considered to be sporadic. Recently, we reported that 2% of CH patients with TD have a positive familial history. The aim of this study was to describe the clinical characteristics of these familial cases and to compare them with sporadic cases. We used the French national population-based registry of the first 19-yr screening program, which included 14,416,428 screened neonates with a 100% recovery rate. Familial history of CH with TD was investigated by means of a questionnaire sent to the pediatricians (n = 592) who provided ongoing clinical care for the 4049 CH patients detected during this period, including 2863 CH cases due to TD. Information was obtained from 73% of these pediatricians who were following up 2472 CH patients with TD (86%). In all, 67 patients with a positive family history of CH with TD were referred, belonging to 32 multiplex families (i.e. including at least 2 affected members). Families were identified with ectopic gland (n = 12), athyreosis (n = 7), or both (n = 13). Comparison of familial with isolated cases showed a similar etiological diagnosis distribution of CH (40% vs. 33% for athyreosis and 60% vs. 67% for ectopic thyroid gland, respectively), whereas a significantly lower predominance of females was found in familial than in isolated cases (1.4 vs. 2.7; P < 0.03). Extrathyroidal congenital malformations were found with a similarly higher incidence in familial and isolated CH populations compared with the general population (respectively, 9% and 8.2% vs. 2.5%). In conclusion, although familial cases represent a minority of cases of congenital hypothyroidism caused by thyroid dysgenesis, they were observed in a significantly higher proportion (>15-fold) than would be expected from chance alone. This familial clustering, including athyreosis and ectopic thyroid gland, strongly suggests that genetic factors could be involved in thyroid dysgenesis with a common underlying mechanism for both etiological groups. Moreover, the high proportion of extrathyroidal congenital malformations in a population affected by CH due to TD suggests that the potential genetic factors involved in thyroid gland organogenesis are also involved in the development of other organs.
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Hipotiroidismo Congénito , Glándula Tiroides/anomalías , Femenino , Humanos , Hipotiroidismo/genética , Masculino , Distribución por SexoAsunto(s)
Mutación de Línea Germinal , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Niño , Salud de la Familia , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Neoplasias/diagnóstico , Neoplasias/genética , Valor Predictivo de las Pruebas , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: A case-control study was carried out to investigate the role of a family history of solid tumor or hematologic neoplasm in the etiology of childhood acute leukemia. METHODS: Family cancer history in first- and second-degree relatives was compared in 279 incident cases (242 cases of acute lymphocytic leukemia and 37 of acute myeloid leukemia) and 285 controls. Recruitment was stratified by age, gender, hospital, area of residence, and ethnic origin. Odds ratios (OR) were estimated using an unconditional regression model taking into account the stratification variables, socioeconomic status, and familial structure. RESULTS: A significant association between childhood acute leukemia and a family history of hematologic neoplasm (OR = 2.7, confidence interval (CI) = 1.1-6.9) was found. This association was particularly clear-cut when the cases were restricted to acute myeloid leukemia (OR = 13.3, CI = 2.5-70.9). Childhood acute leukemia was associated with a family history of solid tumor (OR = 1.5, CI = 1.0-2.2), and elevated odds ratios were observed for family history of gastrointestinal cancer and melanoma. Those results are most unlikely to be explained by socioeconomic status and familial structure, which were very similar for the cases and controls. Differential misclassification is also unlikely for the first-degree relatives, even though it is difficult to rule it out for the second-degree relatives' history. CONCLUSION: The present study supports the hypothesis that a family history of cancer may be a risk factor for childhood acute leukemia.