RESUMEN
Fanconi anemia (FA) and Bloom syndrome (BS) are rare autosomal recessive genetic disorders manifesting in childhood, with a predisposition to cancer development in adolescence and adulthood. Both syndromes are relatively prevalent among the Ashkenazi Jewish population, and, in both syndromes, mutations specific to this population have been identified. Similarly, unique Ashkenazi mutations were found in the genes BRCA1 and BRCA2. These two genes, when mutated, play important roles in familial breast and ovarian carcinogenesis. The genes involved in the pathogenesis of the FA and BS belong to the general class of instability genes. Heterozygosity for the FA gene has no known promalignant potential, while the BS mutation carrier state was associated with an increased frequency of colorectal cancer. The especially frequent carrier state among the Ashkenazi Jewish population coupled with the high prevalence of BRCA1 and BRCA2 in the same population has led us to search for coinheritance affecting the potential for cancer development. One hundred Ashkenazi women with known BRCA1 and BRCA2 mutations were screened for the FA mutation IVS4+4 A-->T and the BS mutation blm(Ash). Our results indicate that there is an increased prevalence of both FA and BS mutation carriers among the population studied compared with the general Ashkenazi population (prevalence of FA mutation 4/100 women [4%] as compared to 35/3104 previously published controls [1.1%], P=0.031, and for BS mutation 3/100 [3.2%] as compared to 36/4001 [0.9%], P=0.058). There was no statistically significant effect of the coinheritance on cancer prevalence, type of cancer, or age of cancer onset. Coinheritance of FA and/or BS mutations seems to be more prevalent among BRCA mutation carriers, but a larger study encompassing more women may help in clarifying this issue.
Asunto(s)
Síndrome de Bloom/genética , Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Judíos/genética , Neoplasias/genética , Síndrome de Bloom/etnología , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Anemia de Fanconi/etnología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Pruebas Genéticas , Mutación de Línea Germinal , Humanos , Israel/epidemiología , Persona de Mediana Edad , Neoplasias/etnología , Neoplasias Ováricas/etnología , Neoplasias Ováricas/genética , Prevalencia , RiesgoRESUMEN
A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some non-Ashkenazi individuals led us to hypothesize that within the Jewish people, the I1307K polymorphism may reflect a founder mutation, and that the mutation is not restricted to ethnic Ashkenazis. To test that notion, and to establish the occurrence rate of the I1307K polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and Moroccan Jews and consecutive Jewish CRC patients and performed haplotype analysis with APC-linked markers in two I1307K carrier families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148 Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi). The mutation detection scheme included PCR followed by denaturing gradient gel electrophoresis (DGGE) or modified restriction analysis (MRA). Haplotypes were assessed using three intragenic and three flanking markers. The I1307K polymorphism was detected in 29/227 Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2 individuals each (approximately 1%) within the Moroccan and Iraqi populations. Allelic pattern analysis in all our I1307K carriers, revealed a common haplotype for the three intragenic markers tested, in all mutation carriers, regardless of ethnic origin. The I1307K polymorphism, therefore, exists in all ethnic Jewish populations: Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K mutation carriers share a common allelic pattern with APC-linked markers. This strongly supports the notion of a founder mutation for I1307K.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Efecto Fundador , Genes APC , Judíos/genética , Mutación Missense , Polimorfismo Genético , Adenocarcinoma/etnología , Adenocarcinoma/genética , Poliposis Adenomatosa del Colon/etnología , Sustitución de Aminoácidos , Neoplasias Colorrectales/etnología , Neoplasias Colorrectales/genética , Europa Oriental/etnología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos/genética , Humanos , Irak/etnología , Israel/epidemiología , Judíos/clasificación , Masculino , Marruecos/etnología , Linaje , PrevalenciaRESUMEN
The frequency of the APC I1307K mutation and its association with disease pattern was examined in 996 Ashkenazi women consisting of individuals with either sporadic (n = 382) or hereditary (n = 143) breast and/or ovarian cancer; asymptomatic BRCA1/2 mutation carriers (185delAG, 5382insC and 6174delT) (n= 53) and healthy controls (n= 418). The I1307K allele was equally distributed among women with sporadic (17/382; 4.6%) and inherited (10/143; 7%) breast and/or ovarian cancer irrespective of their being diagnosed before or after 42 years of age and among asymptomatic (7/53; 13.2%) and cancer manifesting BRCA1/2 carriers (10/143; 7%). Taken together, the prevalence of the I1307K allele was significantly higher in BRCA1/2 carriers compared to non-BRCA1/2 carriers (17/196; 8.7% and 40/800, 5%; respectively). The high prevalence of the I1307K allele among BRCA1/2 carriers is not associated with increased cancer risk but seems to be genetically connected because of Jewish ancestry.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas del Citoesqueleto/genética , Mutación , Neoplasias Ováricas/genética , Proteína de la Poliposis Adenomatosa del Colon , Adulto , Anciano , Anciano de 80 o más Años , Proteína BRCA1/genética , Proteína BRCA2 , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Factores de Transcripción/genéticaAsunto(s)
Citocromo P-450 CYP1A1/genética , Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Reacción en Cadena de la Polimerasa/métodos , Cromosomas Humanos Par 15 , Citocromo P-450 CYP1A1/metabolismo , Humanos , Israel , Datos de Secuencia Molecular , Mutación Missense , Polimorfismo GenéticoRESUMEN
A common germline missense mutation within the APC gene, I1307K, has recently been described in Ashkenazi Jews. We detected this polymorphism in two non-Ashkenazi Jewish women using denaturing gradient gel electrophoresis (DGGE), and hypothesized that in Jewish individuals it might not be restricted to Ashkenazim, and actually reflect a common ancestral polymorphism. To test this notion we performed allelic pattern determination using APC-linked markers in these two women and in nine Ashkenazi carrier controls. The pattern of the intragenic markers, as well as a single downstream marker 30-70 Kb from the APC gene was identical in all individuals, regardless of ethnic origin. We conclude that the I1307K polymorphism in Jewish individuals, is not restricted to Ashkenazim and probably reflects a founder mutation.
Asunto(s)
Genes APC , Judíos , Polimorfismo Genético , Femenino , Tamización de Portadores Genéticos , Mutación de Línea Germinal , Humanos , Masculino , Mutación Missense , LinajeRESUMEN
Biochemical markers for Alzheimer's disease (AD) are of great value for precise diagnosis and in studies of the pathogenetic processes of this disease. A new biochemical assay allowing to differentiate AD from other forms of dementia is described. The assay is based on the extraction of amyloid beta (A beta) from milligram amounts of brain tissue by using 20% acetonitrile in 0.1% trifluoroacetic acid and its detection by Western blotting. The presence of the 4 kDa A beta was demonstrated in all cases of AD (n = 8) that were diagnosed by the independent histopathological examination of the postmortem tissues. No A beta was found in tissue extracts from seven out of eight cases of other forms of dementia. In contrast to other biochemical techniques of A beta detection in brain, the developed assay is simple; it does not require any special equipment and allows detection of A beta using milligram amounts of brain tissue.