Genomic rearrangements in BRCA1 and BRCA2: A literature review

Abstract

Women with mutations in the breast cancer genes BRCA1 or BRCA2 have an increased lifetime risk of developing breast, ovarian and other BRCA-associated cancers. However, the number of detected germline mutations in families with hereditary breast and ovarian cancer (HBOC) syndrome is lower than expected based upon genetic linkage data. Undetected deleterious mutations in the BRCA genes in some high-risk families are due to the presence of intragenic rearrangements such as deletions, duplications or insertions that span whole exons. This article reviews the molecular aspects of BRCA1 and BRCA2 rearrangements and their frequency among different populations. An overview of the techniques used to screen for large rearrangements in BRCA1 and BRCA2 is also presented. The detection of rearrangements in BRCA genes, especially BRCA1, offers a promising outlook for mutation screening in clinical practice, particularly in HBOC families that test negative for a germline mutation assessed by traditional methods.

Keywords: BRCA1; BRCA2; MLPA; breast cancer; genomic rearrangements.

Figure 1

Alu elements in BRCA1 (reproduced from Pavlicek et al. 2004, by permission of Oxford University Press). Exons are depicted as red rectangles and Alu sequences as arrows. Alu elements known to be involved in human exonic deletions and/or duplications are shown in blue.

Figure 2

Suggested approach for molecular investigation of hereditary breast and ovarian cancer (HBOC) families. The mutation probabilities are estimated by using standard protocols and/or risk estimation tools such as BRCAPro, BOADICEA and the Myriad mutation prevalence tables. ASCO: American Society of Clinical Oncology.