Background: It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in theBRCA1andBRCA2genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e.,BRIP1,RAD51C, andRAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed toBRIP1,RAD51C, andRAD51Dmutations, we performed a meta-analysis based on a comparison of a total of ~ 29,400 ovarian cancer patients from 63 studies and a total of ~ 116,000 controls from the gnomAD database.Results: The analysis allowed precise estimation of ovarian cancer risks attributed to mutations inBRIP1,RAD51C, andRAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07–6.00,p < 0.0001; OR = 5.59, 95%CIs:4.42–7.07,p < 0.0001; and OR = 6.94, 95%CIs:5.10–9.44,p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes.Conclusions: The meta-analysis provides evidence supporting the pathogenicity ofBRIP1,RAD51C, andRAD51Dmutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that afterBRCA1andBRCA2, theBRIP1,RAD51C, andRAD51Dgenes are the most important ovarian cancer risk genes, cumulatively contributing to ~ 2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.

For nearly two decades most research on BARD1 was closely linked to research on BRCA1, the breast cancer predisposition gene. The co-expression of BARD1 and BRCA1 genes in most tissues, the nearly identical phenotype of Bard1 and Brca1 knock-out mice, and the fact that BRCA1 and BARD1 proteins form a stable complex, led to the general assumption that BARD1 acts as an accessory to BRCA1. More recent research on both proteins showed that BRCA1 and BARD1 might have common as well as separate functions. This review is an overview of how BARD1 functions and controls BRCA1. It highlights also experimental evidence for dominant negative, tumor promoting, functions of aberrant isoforms of BARD1 that are associated with and drivers of various types of cancer.

Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.

Detection of BRCA1/2 mutations in circulating tumor DNA from patients with ovarian cancer Detection of BRCA1/2 mutations in circulating tumor DNA from patients with ovarian cancer