BRCA2 related cancer, haploinsufficiency and telomere dysfunction

Abstract

Germline mutations in BRCA2 increase the risk of breast and ovarian cancer. The BRCA2 protein is involved in maintaining genomic stability through its roles in DNA double strand break repair and protection of stalled replication forks. The BRCA2 gene is considered a classical tumor suppressor gene and loss of heterozygosity (LOH) is generally assumed in malignant tumors. However, retention of the wild type allele is observed in a subset of tumors from mutation carriers, suggesting BRCA2 haploinsufficiency. Icelandic cohorts of ovarian cancer and male breast cancer were screened for the BRCA2 999del5 founder mutation. Locus specific LOH was found present in a large majority of tumors in both cohorts. In contrast, retention of the wild-type allele has been shown to occur in up to half of female breast tumors from BRCA2 mutation carriers. This highlights heterogeneous tumor development and/or progression pathways between tissues and indicates tissue-specific BRCA2 haploinsufficiency in the female breast. Cells lacking BRCA2 develop telomere abnormalities. Focusing on a possible haploinsufficiency effect on telomeres in female BRCA2 mutation carriers, shorter telomere length in both blood and normal breast tissue was associated with earlier breast cancer occurrence in BRCA2 mutation carriers but not in non-carriers. Short telomeres are often indicative of dysfunctional telomere maintenance. Additionally, short telomeres and high levels of DNA damage were observed in luminal epithelial cells in normal breast tissue which is highly relevant as these are the cells from which most breast cancers arise.