A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families.
We have analyzed 20 breast-ovarian cancer families, the majority of which show positive evidence of linkage to chromosome 17q12 for germ-line mutations in the BRCA1 gene. BRCA1 mutations cosegregating with breast and ovarian cancer susceptibility were identified in 16 families, including 1 family with a case of male breast cancer. Nine of these mutations have not been reported previously. The majority of mutations were found to generate a premature stop codon leading to the formation of a truncated BRCA1 protein of 2%-88% of the expected normal length. Two mutations altered the RING finger domain. Sequencing of genomic DNA led to the identification of a mutation in the coding region of BRCA1 in 12 families, and cDNA analysis revealed an abnormal or missing BRCA1 transcript in 4 of the 8 remaining families. A total of eight mutations were associated with a reduced quantity of BRCA1 transcript. We were unable to detect BRCA1 mutations in 4 of the 20 families, but only 1 of these was clearly linked to BRCA1. It is expected that the majority of clear examples of the breast-ovarian syndrome will be associated with germ-line mutations in the coding region of BRCA1.
Serova
O
O
International Agency for Research on Cancer, Lyon, France.
Montagna
M
M
Torchard
D
D
Narod
S A
SA
Tonin
P
P
Sylla
B
B
Lynch
H T
HT
Feunteun
J
J
Lenoir
G M
GM
D017398:Alternative Splicing; D019313:BRCA1 Protein; D001943:Breast Neoplasms / Q000235:genetics*; D002874:Chromosome Mapping; D002886:Chromosomes, Human, Pair 17; D003062:Codon; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D005817:Genetic Counseling; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
D019313:BRCA1 Protein; D003062:Codon; D009363:Neoplasm Proteins; D014157:Transcription Factors