DISTINCT SOMATIC GENETIC CHANGES ASSOCIATED WITH TUMOR PROGRESSION INCARRIERS OF BRCA1 AND BRCA2 GERM-LINE MUTATIONS

BRCA1 and BRCA2 mutations confer increased risk for development of bre ast cancer, but a number of additional, currently largely unknown, som atic genetic defects must also accumulate in the breast epithelial cel ls before malignancy develops. To evaluate the nature of these additio nal somatic genetic defects, we performed a genome-wide survey by comp arative genomic hybridization on breast cancers from 21 BRCA1 mutation carriers, 15 BRCA2 mutation carriers, and 55 unselected controls, The total number of genetic changes was almost two times higher in tumors from both BRCA1 and BRCA2 mutation carriers than in the control group . In BRCA1 tumors, losses of 5q (86%), 4q (81%), 4p (61%), 2q (40%), a nd 12q (40%) were significantly more common than in the control group (7-13%). BRCA2 tumors were characterized by a higher frequency of 13q (73%) and 6q (60%) losses and gains of 1.7q22-q24 (87%) and 20q13 (60% ) as compared to the prevalence of these changes in the control group (12-18%). In conclusion, accumulation of somatic genetic changes durin g tumor progression may follow a unique pathway in individuals genetic ally predisposed to cancer, especially by the BRCA1 gene, Activation o r loss of genes in the affected chromosomal regions may be selected fo r during tumor progression in cells lacking functional BRCA1 or BRCA2. Identification of such genes could provide targets for therapeutic in tervention and early diagnosis.