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BRCA1, BRCA2, CHEK2 and PALB2 genes are associated with hereditary breast and ovarian cancer syndrome. Genetic testing of these genes is of increasing importance to guide therapeutic and management decisions. In this study, we evaluated the performance of a next generation sequencing (NGS) assay for the complete analysis of BRCA1, BRCA2, CHEK2 and PALB2 genes using Agilent's SureMASTR BRCA Screen that enabled the detection of single nucleotide variants (SNVs), small insertions/deletions (indels) and copy number variations (CNVs) in a single-tube PCR based library preparation. The results showed 100% sensitivity and specificity on a set of 52 known samples from de-identified patients and external quality assessment program. A concordance rate of 87.5% was achieved in the comparison of variant classification with the external laboratories. The high accuracy of the assay supports the use of SureMASTR BRCA Screen in clinical diagnostic laboratories (SureMASTR BRCA Screen is for research use only, not for use in diagnostic procedures).

Objective To evaluate the feasibility of detecting actionable gene mutations in circulating tumor DNA (ctDNA) in patients with advanced non-small-cell lung cancer (NSCLC) using targeted next-generation sequencing (NGS). Materials and methods In total 50 plasma samples from patients newly diagnosed with advanced NSCLC or resistant to first-line tyrosine kinase inhibitors (TKIs) were subjected to deep sequencing on a seven-gene panel (BRAF, EGFR, ERBB2, KRAS, NRAS, PIK3CA, PTEN) incorporated with molecular barcodes to improve accuracy in variant detection. When possible, results were compared with those from matched tissue samples. Results At least one alteration in the ctDNA was detected in 44 out of 50 patients (88%); EGFR was the most frequently mutated gene. Half the total number of patients (50%, 25 of 50) had at least one actionable genetic alteration with targeted therapies available for treatment. Our results showed a high concordance rate of 81% in detection of EGFR mutation between 26 matched tissue and plasma samples. For progressive patients, from whom tissue is mostly unavailable, the resistant EGFR T790 M mutation was validated using the droplet digital polymerase chain reaction (ddPCR), yielding a concordance of 92% between alternative platforms. Conclusion Our study demonstrated that therapeutically actionable mutations can be detected with high accuracy in ctDNA using NGS. This promising approach offers alternative and non-invasive diagnostic methods for treatment guidance and clinical monitoring.

Underrepresentation of Asian genomes has hindered population and medical genetics research on Asians, leading to population disparities in precision medicine. By whole-genome sequencing of 4,810 Singapore Chinese, Malays, and Indians, we found 98.3 million SNPs and small insertions or deletions, over half of which are novel. Population structure analysis demonstrated great representation of Asian genetic diversity by three ethnicities in Singapore and revealed a Malay-related novel ancestry component. Furthermore, demographic inference suggested that Malays split from Chinese ∼24,800 years ago and experienced significant admixture with East Asians ∼1,700 years ago, coinciding with the Austronesian expansion. Additionally, we identified 20 candidate loci for natural selection, 14 of which harbored robust associations with complex traits and diseases. Finally, we show that our data can substantially improve genotype imputation in diverse Asian and Oceanian populations. These results highlight the value of our data as a resource to empower human genetics discovery across broad geographic regions. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Accepted version We acknowledge H.M. Kang, S. Das, A. Tan, F. Zhang, J. Terhorst, P.-R. Loh, and G. Hellenthal for helpful discussions and support from all participants and clinical research coordinators of the contributing cohorts and studies: the TTSH Healthy Control Workgroup, the SEED cohort, the Asian Sudden Cardiac Death in Heart Failure Study, the Singapore Heart Failure Outcomes and Phenotypes (SHOP) cohort, the Asian neTwork for Translational Research and Cardiovascular Trials (ATTRaCT), the Parkinson’s Disease Study, the Peranakan Genome Study, the Platinum Asian Genomes Project, the Bariatric Surgery Study, the National Heart Centre Singapore Biobank and SingHEART cohorts, and the GUSTO and S-PRESTO study groups. This study was supported by Singapore’s A*STAR (core funding and IAF-PP H17/01/a0/007), BMRC (SPF2014/001, SPF2013/002, SPF2014/003, SPF2014/004, and SPF2014/005), NMRC (CIRG/1371/2013, CIRG/1417/2015, CIRG/1488/ 2018, CSA-SI/0012/2017, CG/017/2013, CG/M006/2017_NHCS, TCR/013- NNI/2014, STaR/0011/2012, STaR2013/001, STaR/014/2013, STaR/0026/ 2015, TCR/006-NUHS/2013, TCR/012-NUHS/2014, TCR/004-NUS/2008, TCR/012-NUHS/2014, and center grants 2010-13 and 2013-2017), NRF (NRFF2016-03), National University of Singapore, SingHealth and DukeNUS, and Alexandra Health small innovative grant SIGII/15203 and funding from Huazhong University of Science and Technology, the Tanoto Foundation, the Lee Foundation, the Boston Scientific Investigator Sponsored Research Program and Bayer, the NSF (DEB-1753489), and the Alfred P. Sloan Foundation. The computation was partially performed on resources of the National Supercomputing Centre, Singapore (https://www.nscc.sg).

Introduction While overexpression of syndecan-1 has been associated with aggressive breast cancer in the Caucasian population, the expression pattern of syndecan-1 in Asian women remains unclear. Triple-positive breast carcinoma, in particular, is a unique subtype that has not been extensively studied. We aimed to evaluate the role of syndecan-1 as a potential biomarker and prognostic factor for triple-positive breast carcinoma in Asian women. Methods Using immunohistochemistry, staining scores of 61 triple‑positive breast carcinoma specimens were correlated with patients' clinicopathological variables such as age, ethnicity, tumour size, histological grade, lymph node status, lymphovascular invasion, associated ductal carcinoma in situ grade, recurrence and overall survival. Results Syndecan-1 had intense staining scores in triple‑positive invasive ductal breast carcinomas when compared to normal breast tissue. On multivariate analysis, syndecan-1 epithelial total percentage and immunoreactivity score showed statistical correlation with survival (p = 0.02). Conclusion The intense staining scores of syndecan-1 and their correlation with overall survival in patients with triple-positive breast carcinoma suggest that syndecan-1 may have a role as a biological and prognostic marker in patients with this specific subtype of breast cancer.