A systematic review on the frequency of BRCA promoter methylation in breast and ovarian carcinomas of BRCA germline mutation carriers : Mutually exclusive, or not?

Background: A considerable number of breast and ovarian carcinomas are due to underlying BRCA gene aberrations. Of these, BRCA germline mutations and BRCA promoter methylation are thought to be mutually exclusive, which could be exploited in clinical practice. However, this paradigm has not been studied extensively and systematically. Objective: To systematically investigate to what extent BRCA promoter methylation has been reported in breast and ovarian carcinomas of BRCA germline mutation carriers. Methods: A comprehensive search on BRCA promoter methylation was performed in PubMed and Embase databases. Two authors independently selected studies, assessed study quality and extracted data according to PRISMA and QUADAS-2 guidelines. Results: 21 articles met the inclusion criteria. BRCA1 methylation was found in at least 10/276 (3,6%) breast and 2/174 (1,1%) ovarian carcinomas of BRCA germline mutation carriers, and BRCA2 methylation was found in at least 7/131 (5.3%) breast and 0/51 (0.0%) ovarian carcinomas of BRCA germline mutation carriers. Methylation frequencies varied between individual CpG sites. The selected studies showed important differences in methodology and performed in general a limited methylation and incomplete mutation analysis. Conclusions: BRCA methylation is rare in breast and ovarian carcinomas of BRCA germline mutation carriers, although the frequency of BRCA promoter methylation may be underestimated. This could have major implications for clinical practice, including referral for genetic testing and BRCAness analysis for treatment decision-making

BRCA promoter methylation in sporadic versus BRCA germline mutation-related breast cancers

Background: In breast cancer, BRCA promoter hypermethylation and BRCA germline mutations are said to occur together rarely, but this property has not yet been translated into a clinical test. Our aim in this study was to investigate the diagnostic value of BRCA1/2 methylation in distinguishing breast carcinomas of BRCA1 and BRCA2 germline mutation carriers from sporadic breast carcinomas using a recently developed BRCA methylation assay based on methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methods: MS-MLPAs were performed to assess BRCA1 and BRCA2 methylation in breast carcinoma tissues from 39 BRCA1 and 33 BRCA2 germline mutation carriers, 80 patients with sporadic breast cancer, and normal breast tissues from 5 BRCA1 and 4 BRCA2 mutation carriers and 5 nonmutation carriers. Results: Methylation frequencies varied considerably between CpG sites across the BRCA1 and BRCA2 promoters. Some CpG sites were methylated more frequently in BRCA1/2-related than in sporadic carcinomas, whereas other CpG sites were methylated more frequently in sporadic carcinomas, with large variances in sensitivity and specificity as a consequence. Conclusions: The diagnostic value of BRCA promoter methylation analysis in distinguishing BRCA1/2-related from sporadic breast carcinomas seems to be considerably dependent on the targeted CpG sites. These findings are important for adequate use of BRCA methylation analysis as a prescreening tool for BRCA germline genetic testing or to identify BRCAness patients who may benefit from targeted therapies such as poly(adenosine diphosphate-ribose) polymerase inhibitors

The microRNA Lifecycle in Health and Cancer

MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that regulate gene expression at the post-transcriptional level. They can bind to around 60% of all protein-coding genes with an average of 200 targets per miRNA, indicating their important function within physiological and pathological cellular processes. miRNAs can be quickly produced in high amounts through canonical and non-canonical pathways that involve a multitude of steps and proteins. In cancer, miRNA biogenesis, availability and regulation of target expression can be altered to promote tumour progression. This can be due to genetic causes, such as single nucleotide polymorphisms, epigenetic changes, differences in host gene expression, or chromosomal remodelling. Alternatively, post-transcriptional changes in miRNA stability, and defective or absent components and mediators of the miRNA-induced silencing complex can lead to altered miRNA function. This review provides an overview of the current knowledge on the lifecycle of miRNAs in health and cancer. Understanding miRNA function and regulation is fundamental prior to potential future application of miRNAs as cancer biomarkers