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 (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, ie., 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.
Sobol
H
H
Department of Genetic Oncology and Laboratory of Tumor Biology, Paoli-Calmettes Institute, INSERM U 119, France.
Stoppa-Lyonnet
D
D
Bressac-de-Paillerets
B
B
Peyrat
J P
JP
Kerangueven
F
F
Janin
N
N
Noguchi
T
T
Eisinger
F
F
Guinebretiere
J M
JM
Jacquemier
J
J
Birnbaum
D
D
D000483:Alleles; D019313:BRCA1 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics; D017384:Sequence Deletion; D014157:Transcription Factors / Q000502:physiology*
D019313:BRCA1 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors