TRUNCATION AT CONSERVED TERMINAL REGIONS OF BRCA1 PROTEIN IS ASSOCIATED WITH HIGHLY PROLIFERATING HEREDITARY BREAST CANCERS

The existence of two subgroups of BRCA1-associated breast cancer (EC) families has been recently posited: the first with highly proliferatin g tumors, and the second composed of cases with a low proliferation ra te, Our aim was to test whether the proliferation rate of BRCA1-associ ated breast cancers was affected by the site of the germ line mutation in the BRCA1 gene, We analyzed the distribution of the mitotic index, a histoprognostic grade component shown to segregate in families, mat ching for germ line mutation Location in a series of 28 breast cancers from 20 kindreds. We observed a prevalence of highly proliferating tu mors when the mutation occurs in the two terminal conserved domains of the BRCA1 protein, i.e., in the amino and carboxyl termini (P = 0.002 4). Our data provide evidence for a genotype-phenotype correlation and along with their strong conservation during evolution argue for the i mportance of these two regions in the control of mammary cell growth.