Introduction: About 5-10% of breast cancer cases occur in a familial setting compatible with a hereditary origin. Approximately 40% of these can be traced to germline mutations in the BRCA1 and BRCA2 susceptibility genes. So far, no other major BRCA genes that account for the remaining non-BRCA1/2 group have been found.

The aim of this study is to compare the frequency and distribution of genomic aberrations in breast tumors from families with 1) germline mutation in the BRCA1- or BRCA2-gene, 2) high frequency of breast cancer without BRCA1/2 mutation (BRCAX) and 3) sporadic breast cancer.

Methods: DNA was isolated from fresh-frozen tumor tissue: BRCA1 (n=24), BRCA2 (n=45), BRCAX (n=89) and sporadic (n=53). We employed high resolution array-CGH with over 32.400 BAC-clones that cover the genome at an average resolution of about 45 kb. The arrays were scanned (Agilent microarray scanner), the images edited (GenePix Pro) and uploaded to BASE (Bio Array Software Environment) where data was background corrected and normalized. CGH-plotter software was used for breakpoint analysis of chromosomal aberrations. A two-sided Mann-Whitney test was used to calculate significant differences in copy number frequency between groups.

Results: The frequency of genomic aberrations is more elevated within the BRCA1- and BRCA2 tumor groups compared to the BRCAX and sporadic. In comparison to the sporadic tumor group, copy number losses on chromosome 4 and 5q are the most distinctive feature for the BRCA1 group while copy number gains on 8q and 20q, and copy number losses on 13q characterize the BRCA2 group. The genomic profile of the BRCAX- and the sporadic group is similar both regarding the frequency and locations of aberrations. Frequent aberrations for both groups are copy number gains on 1q, 8q and 16p and copy number losses on 8p, 11q and 16q.

Conclusion: The results indicate that most of the genomic regions that affect the development of breast cancer in families not affected by mutations in the BRCA1 or BRCA2 genes are the same as in sporadic tumors. They also confirm the high frequency of aberrations in BRCA1 and BRCA2 tumors which reflects their importance in DNA-repair.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA