BRCA1/2 Haploinsufficiency: Exploring the Impact of Losing one Allele

Since their discovery in the late 20^th century, significant progress has been made in elucidating the functions of the tumor suppressor proteins BRCA1 and BRCA2. These proteins play vital roles in maintaining genome integrity, including DNA repair, replication fork protection, and chromosome maintenance. It is well-established that germline mutations in BRCA1 and BRCA2 increase the risk of breast and ovarian cancer; however, the precise mechanism underlying tumor formation in this context is not fully understood. Contrary to the long-standing belief that the loss of the second wild-type allele is necessary for tumor development, a growing body of evidence suggests that tumorigenesis can occur despite the presence of a single functional allele. This entails that heterozygosity in BRCA1/2 confers haploinsufficiency, where a single copy of the gene is not sufficient to fully suppress tumor formation. Here we provide an overview of the findings and the ongoing debate regarding BRCA haploinsufficiency. We further put out the challenges in studying this topic and discuss its potential relevance in the prevention and treatment of BRCA-related cancers.