RESUMEN
The breast cancer predisposing gene, BRCA1, was analyzed for germline mutations in 45 African American families at high-risk for hereditary breast cancer. Patients were considered high-risk if they had a family history of the disease, early onset breast cancer, bilateral breast cancer, or breast and ovarian cancer. The entire BRCA1 coding and flanking intron regions have been examined by single stranded conformation polymorphism analysis followed by sequencing of variant bands. Eleven different BRCA1 germline mutations/variations were identified in 7 patients from the 45 high-risk families. Two pathogenic, protein-truncating mutations were detected in exon 11. A ten base pair tandem duplication, 943ins10, was present in a woman with breast and ovarian cancer whose first-degree relatives had prostate cancer. A four base pair deletion, 3450del4, was detected in a breast cancer patient with five cases of breast cancer in the family; two of the proband's sisters with breast cancer also carried the same mutation. Four amino acid substitutions (Lys1183Arg, Leu1564Pro, Gln1785His, and Glu1794Asp) and four nucleotide substitutions in intron 22 (IVS22+78 C/A, IVS22+67 T/C, IVS22+8 T/A and IVS22+7 T/C) were observed in patients and not in control subjects. One early onset breast cancer patient carried five distinct BRCA1 variations, two amino acid substitutions and three substitutions in intron 22. An amino acid substitution in exon 11, Ser1140Gly, was identified in 3 different unrelated patients and in 6 of 92 control samples. The latter probably represents a benign polymorphism.
Asunto(s)
Población Negra/genética , Neoplasias de la Mama/genética , Genes BRCA1/genética , Mutación , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama Masculina/genética , Análisis Mutacional de ADN , Femenino , Humanos , Intrones , Masculino , Persona de Mediana Edad , Neoplasias Ováricas/genética , Linaje , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , Neoplasias de la Próstata/genética , Factores de Riesgo , Estados UnidosRESUMEN
Due to a deficiency in mitochondrial protein synthesis, Chinese hamster lung (CHL) cell mutant Gal- 32 does not grow in galactose or fructose. This report examines the nuclear or cytoplasmic inheritance of this single, recessive mutation. In a control experiment, fusion of Gal+TGSTK- cells with Gal- 32TGRTK+ cells resulted in tetraploid hybrids (as verified by karyotyping) that were selected in hypoxanthine/aminopterin/thymidine medium. The majority (2/3) of the control hybrids grew in galactose as expected since Gal+ is dominant over Gal-. Fusion of Rhodamine 6-G treated Gal+TGSTK- cells with Gal- 32TGRTK+ cells resulted in Rhodamine 6-G-tetraploid hybrids that were selected in hypoxanthine/aminopterin/thymidine medium. The majority (7/12) of the Rhodamine 6-G-hybrids grew in galactose as expected for a nuclearly encoded gene considering that Rhodamine 6-G interferes with transmission of mtDNA but not nuclear DNA. Therefore, these results are compelling in their demonstration of the nuclear origin of the Gal- 32 mutation.