RESUMEN
PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.
Asunto(s)
Proteína BRCA2 , Neoplasias de la Mama Masculina , Neoplasias de la Mama , Judíos , Proteína BRCA2/genética , Neoplasias de la Mama/etnología , Neoplasias de la Mama/genética , Neoplasias de la Mama Masculina/etnología , Neoplasias de la Mama Masculina/genética , Etiopía/epidemiología , Femenino , Efecto Fundador , Predisposición Genética a la Enfermedad , Humanos , Judíos/genética , Masculino , Estudios RetrospectivosRESUMEN
Fragile X syndrome (Fra X) is the most common heritable disease accounting for mental retardation and is caused by an expanded CGG repeat in the first exon of the FMR1gene. Previous studies have shown an increased fertility rate among fragile X carrier mothers and a preponderance of mentally retarded boys among the male offspring. In this study, we examined the transmission of the intermediate allele in the lower range of CGG repeats in carrier mothers found randomly in a screening program of the normal population. We tested 10,587 healthy women with no family history of mental retardation and identified 138 (1.3%) who were carriers of the intermediate allele (51-200 CGG repeats). Of these, 107 underwent prenatal testing during 108 pregnancies for Fra X in the fetus. Of the 108 pregnancies, the abnormal allele was transmitted in 67 (segregation ratio = 0.62, P < 0.012). We found a significant increase in the transmission of the abnormal allele by mothers who had between 51 and 60 repeats (segregation ratio = 0.69 [P < 0.007] for the group with 51-55 repeats, and 0.74 [P < 0.04] for the group with 56-60 repeats), but no increase by mothers who had more than 61 repeats. This suggests a genetic advantage for the abnormal allele in the 51- to 60-repeat range.
