HIGH PROPORTION OF MISSENSE MUTATIONS OF THE BRCA1 AND BRCA2 GENES INJAPANESE BREAST-CANCER FAMILIES

Mutations in either of two recently identified genes, BRCA1 and BRCA2, are thought to be responsible for approximately two-thirds of all cas es of autosomal-dominantly inherited breast cancer. To examine the nat ure and frequency of BRCA1 and BRCA2 mutations in Japanese families ex hibiting a high incidence of breast cancer, we screened 78 unrelated f amilies in this category for mutations of these two genes. Examining t he entire coding sequences as well as exon-intron boundaries of both g enes by polymerase chain reaction (PCR) single-strand conformation pol ymorphism (SSCP) and multiplex-SSCP analysis, we identified possible d isease-causing alterations in BRCA1 among affected members of 15 famil ies and in BRCA2 in another 14 families. In 15 of those 29 families, t he affected individuals carried missense mutations, although most germ line mutations reported worldwide have been deletions or nonsense muta tions. Our results, indicating that missense mutations of BRCA1 and BR CA2 tend to predominate over frameshifts or nonsense mutations in Japa nese breast cancer families, will contribute significantly to an under standing of mammary tumorigenesis in Japan, and will be of vital impor tance for future genetic testing.