Biology subjects

Yeu, Y.

Publications and source records attributed to Yeu, Y..

4 recordsLinked to original sources

bioRxiv2019

Hispanic/Latino gastric adenocarcinoma patients have distinct molecular profiles including a high rate of germline CDH1 mutations

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes as compared to patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients were included in previous studies. We performed a large, integrated genomic analysis of gastric cancer samples from Hispanic/Latino patients. Whole-exome sequencing (WES) and RNA sequencing were performed on 57 Hispanic/Latino gastric cancer patient samples. Germline analysis was conducted on 83 patients. Functional testing of CDH1 germline mutations was performed in Chinese hamster ovary cells. Tumors from Hispanic/Latino patients were significantly enriched for the genomically-stable subtype (as defined by The Cancer Genome Atlas), compared to Asians and Whites (65% vs 21% vs 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type gastric cancer, 7 (16%) had germline mutations in CDH1. Mutation carriers were significantly younger than non-carriers (41 vs 50 years, P < 0.05). E-cadherin expression was reduced in 5 of 6 mutation carrier tumor samples available for analysis. In silico algorithms predicted 5 variants were deleterious. For the two variants that were predicted to be benign, we demonstrated that the mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino gastric cancer patients possess unique genomic landscapes. This includes a high rate of CDH1 germline mutations that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary.

cancer biology↗

bioRxiv2019

CRISPR/Cas9-based mutagenesis frequently provokes on-target mRNA misregulation

The introduction of insertion-deletions (INDELs) by activation of the error-prone non-homologous end-joining (NHEJ) pathway underlies the mechanistic basis of CRISPR/Cas9-directed genome editing. The ability of CRISPR/Cas9 to achieve gene elimination (knockouts) is largely attributed to the emergence of a pre-mature termination codon (PTC) from a frameshift-inducing INDEL that elicits non-sense mediated decay (NMD) of the mutant mRNA. Yet, the impact on gene expression as a consequence of CRISPR/Cas9-introduced INDELs into RNA regulatory sequences has been largely left uninvestigated. By tracking DNA-mRNA-protein relationships in a collection of CRISPR/Cas9-edited cell lines that harbor frameshift-inducing INDELs in various targeted genes, we detected the production of foreign mRNAs or proteins in [~]50% of the cell lines. We demonstrate that these aberrant protein products are derived from the introduction of INDELs that promote internal ribosomal entry, convert pseudo-mRNAs into protein encoding molecules, or induce exon skipping by disruption of exon splicing enhancers (ESEs). Our results using CRISPR/Cas9-introduced INDELs reveal facets of an epigenetic genome buffering apparatus that likely evolved to mitigate the impact of such mutations introduced by pathogens and aberrant DNA damage repair, and that more recently pose challenges to manipulating gene expression outcomes using INDEL-based mutagenesis.

molecular biology↗

bioRxiv2018

Divine: Prioritizing Genes for Rare Mendelian Disease in Whole Exome Sequencing Data

MotivationRecent studies showed that a phenotype-driven analysis of whole exome sequencing (WES) could provide more accurate and clinically relevant genetic variants.\n\nResultsWe develop a computational tool called Divine that integrates patients phenotype(s) and WES data with 30 prior biological knowledge (e.g., human phenotype ontology, gene ontology, pathway database, protein-protein interaction networks, pathogenicity by the amino acid change due to polymorphism, and hot-spot protein domains) to prioritize potential disease-causing genes. In a retrospective study with 22 real and four simulated data set, Divine ranks the same pathogenic genes confirmed by the original studies 5th on average out of a thousand of mutated genes and outperforms existing state-of-the-art methods.\n\nAvailabilityhttps://github.com/hwanglab/divine\n\nContacthwangt@ccf.org\n\nSupplementary informationSupplementary Document is attached at the end of the page.

bioinformatics↗

bioRxiv2017

miR-16 suppresses growth of rhabdoid tumor cells

BackgroundRhabdoid tumor is a highly aggressive pediatric cancer characterized by biallelic loss and/or mutation of SMARCB1. Outcomes remain poor, and there are no established ways to target the tumorigenic pathways driven by SMARCB1 inactivation. SMARCB1 loss leads to an increase in cyclin D transcription.\n\nProcedureWe characterized the cell line WT-CLS1, which has been described previously as Wilms tumor, by whole-exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WT-CLS1, BT-12, and CHLA-06-ATRT.\n\nResultsWe found that WT-CLS1 demonstrates the histological, mutational, and transcriptional hallmarks of rhabdoid tumor. Because the microRNAs let-7 and miR-16 can target cyclin D genes, we next overexpressed each of these microRNAs in WT-CLS1. We found that miR-16 reduced cell accumulation. This was accompanied by a decrease in proliferation markers and an increase in apoptosis markers. These results were replicated in the BT-12 and CHLA-06-ATRT cell lines.\n\nConclusionsThe loss-of-function SMARCB1 mutation found in WT-CLS1, in conjunction with immunohistochemical and gene expression analysis, warrants reclassification of this cell line as rhabdoid tumor. Proliferation of WT-CLS1 and other rhabdoid tumor cell lines is significantly abrogated by miR-16 overexpression. Further studies are necessary to gain insight into the potential for miR-16 to be used as a novel therapeutic in rhabdoid tumor.\n\nAbbreviations

cancer biology↗