BRCA Mutations—The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers

Abstract

Two related tumor suppressor genes, BRCA1 and BRCA2, attract a lot of attention from both fundamental and clinical points of view. Oncogenic hereditary mutations in these genes are firmly linked to the early onset of breast and ovarian cancers. However, the molecular mechanisms that drive extensive mutagenesis in these genes are not known. In this review, we hypothesize that one of the potential mechanisms behind this phenomenon can be mediated by Alu mobile genomic elements. Linking mutations in the BRCA1 and BRCA2 genes to the general mechanisms of genome stability and DNA repair is critical to ensure the rationalized choice of anti-cancer therapy. Accordingly, we review the literature available on the mechanisms of DNA damage repair where these proteins are involved, and how the inactivating mutations in these genes (BRCAness) can be exploited in anti-cancer therapy. We also discuss a hypothesis explaining why breast and ovarian epithelial tissues are preferentially susceptible to mutations in BRCA genes. Finally, we discuss prospective novel therapeutic approaches for treating BRCAness cancers.

A Molecular Characterization of the Allelic Expression of the BRCA1 Founder Δ9–12 Pathogenic Variant and Its Potential Clinical Relevance in Hereditary Cancer

“…It is estimated that 10% of newly diagnosed breast and/or ovarian cancers are hereditary [ 21 ]. HBOC is an inherited predisposition to breast and/or ovarian cancers due to specific gene mutations [ 22 ].…”

A Short Review - Biochemical Aspects and Advancements in Gastric Cancer

“…There is a loss of contact reverse metabolism, hence cancer enhances multilayer growth as a result there is a loss of anchorage dependence. Tumor cells synthesize fetal proteins like alfa fetoprotein generally these genes are suppressed in adult cells 25 .…”

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery

“…Carriers of BRCA1 PGVs show: (i) an absolute risk of BC higher than 60%; (ii) an absolute risk of male BC ranging from 0.2 to 1.2%; and (iii) an absolute risk of epithelial ovarian cancer ranging from 39 to 58%. On the other hand, carriers of BRCA2 PGVs display: (i) an absolute risk of BC higher than 60%; (ii) an absolute risk of male BC ranging from 1.8 to 7.1%; and (iii) an absolute risk of epithelial ovarian cancer ranging from 13 to 29% [5,11,12].…”

“…BRCA1-associated BCs frequently show a ductal histotype, with a negative expression of receptors for estrogen (ER) and progesterone (PR) and absence of HER2/neu amplification ("triple negative" phenotype). Instead, BRCA2-associated BCs have a luminal-like profile, i.e., positivity of ER and/or PR and absence of HER2/neu amplification, as well as a slight incidence increase of the lobular histotype [5,11].…”