The existence of two subgroups of BRCA1-associated breast cancer (BC) families has been recently posited: the first with highly proliferating tumors, and the second composed of cases with a low proliferation rate. Our aim was to test whether the proliferation rate of BRCA1-associated 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, matching for germ line mutation location in a series of 28 breast cancers from 20 kindreds. We observed a prevalence of highly proliferating tumors when the mutation occurs in the two terminal conserved domains of the BRCA1 protein, i.e., in the amino and carboxyl termini (P = 0.0024). Our data provide evidence for a genotype-phenotype correlation and along with their strong conservation during evolution argue for the importance of these two regions in the control of mammary cell growth.

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This work was supported by Paoli-Calmettes Institute, INSERM, and grants from Projet Hospitalier de Recherche Clinique, La Ligue Nationale Contre le Cancer (the national office and the district committees of Alpes de Haute Provence, Bouches du Rhône, Corse du Sud, Haute Corse, Nord, Var), Caisse Nationale d'Assurance Maladie, Federation Nationale des Groupements des Entreprises Francaises dans la Lutte contre le Cancer, Groupements Des Entreprises Francaises Dans la Lutte contre le Cancer Association pour la Recherche sur le Cancer, Fédération Nationale des Centres de Lutte Contre le Cancer, and Groupement de Recherche et d'Etude sur les Génomes.

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