Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations

BRCA1 and BRCA2 mutations confer highly increased risk for development of breast cancer, but a large number of additional, currently largely unknown, somatic genetic defects must also accumulate in the breast epithelial cells before malignancy develops. To evaluate the nature of these additional somatic genetic defects, we performed a genome-wide survey by comparative genomic hybridization (CGH) on breast cancers from 22 BRCA1 carriers, 15 BRCA2 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 (64%), 2q (40%), and 12q (40%) were significantly more common than in the control group (7-13%). BRCA2 tumors were in turn characterized by a high frequency of 13q (73%) and 6q (60%) losses and gains of 17q22-q24 (87%) and 20q13 (60%) as compared to the prevalence of these changes in the control group (12-18%). All three groups showed a similarly high frequency of 17p and 18q loses, as well as gains of 1q and 8q. In conclusion, the multi-step progression process and accumulation of somatic genetic changes appear to follow a unique course in individuals genetically predisposed to cancer, especially by the BRCA1 gene. Genes in the affected chromosomal regions may collaborate with BRCA1 and BRCA2 in the malignant progression.