The identification and interpretation of germline BRCA1/2 variants become increasingly important in breast and ovarian cancer (OC) treatment. However, there is no comprehensive analysis of the germline BRCA1/2 variants in a Chinese population. Here we performed a systematic review and meta-analysis on such variants from 94 publications. A total of 2,128 BRCA1/2 variant records were extracted, including 601 from BRCA1 and 632 from BRCA2. In addition, 414, 734, 449, and 307 variants were also recorded in the BIC, ClinVar, ENIGMA, and UMD databases, respectively, and 579 variants were newly reported. Subsequent analysis showed that the overall germline BRCA1/2 pathogenic variant frequency was 5.7% and 21.8% in Chinese breast and OC, respectively. Populations with high-risk factors exhibited a higher pathogenic variant percentage. Furthermore, the variant profile in Chinese is distinct from that in other ethnic groups with no distinct founder pathogenic variants. We also tested our in-house American College of Medical Genetics-guided pathogenicity interpretation procedure for Chinese BRCA1/2 variants. Our results achieved a consistency of 91.2-97.6% (5-grade classification) or 98.4-100% (2-grade classification) with public databases. In conclusion, this study represents the first comprehensive meta-analysis of Chinese BRCA1/2 variants and validates our in-house pathogenicity interpretation procedure, thereby providing guidance for further PARP inhibitor development and companion diagnostics in the Chinese population.

Abstract. In the present study, the anti-tumor effects of combination treatment with an siRNA targeting B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E and phosphoinositide 3-kinase (PI3K) signaling pathway inhibitors was investigated in melanoma cell lines harboring BRAF V600E . Human melanoma A375 and WM115 cells were treated with siRNA targeting to BRAF or BRAF V600E , combined with treatment with PI3K signaling pathway inhibitors. CCK-8 and EdU proliferation assays were performed to assess cell viability and proliferation, respectively, following treatment. In addition, flow cytometry analysis was performed to determine cell cycle distribution, and western blot analysis was performed to analyze the activity of the extracellular signal-regulated kinase (ERK) and PI3Ksignaling pathways following treatment. Targeting BRAF V600E using small interfering (si)RNA significantly decreased cell viability and DNA replication in tumor cell lines that harbor oncogenic BRAF V600E . Inhibition of BRAF V600E by siRNA combined with treatment with PI3K or mammalian target of rapamycin signaling pathway inhibitors significantly decreased cell viability and proliferation compared with siRNA or inhibitor treatment alone. Concomitant BRAF V600E and PI3K inhibition led to G 1 /S phase arrest in melanoma cells. However, melanoma cells in which oncogenic BRAF V600E is not highly expressed (WM115 cells) were not sensitive to BRAF V600E targeted therapy. The PI3K signaling pathway inhibitors were more effective in this cell line. The results from the present study provide an insight into the potential effectiveness of combination therapy and personalized cancer treatments.

Front Cover: The cover image is based on the Research Article Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients by Xianqi Gao et al., https://doi.org/10.1002/humu.23965. Cover image © Yulong Geng Images

Truncation of BC15 and d-/l-isothymidine modification of its core sequence greatly enhanced the binding affinity and selectivity to the hnRNP A1 protein.