ORCID Profile
0000-0002-6923-4097
Current Organisation
Hong Kong University of Science and Technology
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Publisher: Springer Science and Business Media LLC
Date: 19-03-2021
DOI: 10.1038/S41388-021-01743-3
Abstract: Molecular-based classifications of gastric cancer (GC) were recently proposed, but few of them robustly predict clinical outcomes. While mutation and expression signature of protein-coding genes were used in previous molecular subtyping methods, the noncoding genome in GC remains largely unexplored. Here, we developed the fast long-noncoding RNA analysis (FLORA) method to study RNA sequencing data of GC cases, and prioritized tumor-specific long-noncoding RNAs (lncRNAs) by integrating clinical and multi-omic data. We uncovered 1235 tumor-specific lncRNAs, based on which three subtypes were identified. The lncRNA-based subtype 3 (L3) represented a subgroup of intestinal GC with worse survival, characterized by prevalent TP53 mutations, chromatin instability, hypomethylation, and over-expression of oncogenic lncRNAs. In contrast, the lncRNA-based subtype 1 (L1) has the best survival outcome, while LINC01614 expression further segregated a subgroup of L1 cases with worse survival and increased chance of developing distal metastasis. We demonstrated that LINC01614 over-expression is an independent prognostic factor in L1 and network-based functional prediction implicated its relevance to cell migration. Over-expression and CRISPR-Cas9-guided knockout experiments further validated the functions of LINC01614 in promoting GC cell growth and migration. Altogether, we proposed a lncRNA-based molecular subtype of GC that robustly predicts patient survival and validated LINC01614 as an oncogenic lncRNA that promotes GC proliferation and migration.
Publisher: Springer Science and Business Media LLC
Date: 17-10-2022
DOI: 10.1038/S41388-022-02499-0
Abstract: Papillary thyroid carcinoma (PTC) is heterogeneous and its molecular characteristics remain elusive. We integrated transcriptomic sequencing, genomic analysis and clinicopathologic information from 582 tissue s les of 216 PTC and 75 benign thyroid nodule (BTN) patients. We discovered four subtypes of PTC including Immune-enriched Subtype, BRAF-enriched Subtype, Stromal Subtype and CNV-enriched Subtype. Molecular subtypes were validated in an external cohort of 497 PTC cases from the TCGA. Tumors in the Immune-enriched Subtype showed higher immune infiltration and overexpression of immune checkpoints, whilst BRAF-enriched Subtype showed a higher tendency for extrathyroidal extension and more advanced TNM stage. Key oncogenes including LRRK2, SLC34A2, MUC1, FOXQ1 and KRT19 were overexpressed and enriched in oncogenic MAPK and PI3K/AKT signaling pathways in BRAF-enriched subtype. Further analysis of BRAF-enriched Subtype identified three subclasses with different degrees of malignancies. We also uncovered the molecular link of the initiation and progression from BTN to subtypes of PTC using trajectory analysis. Moreover, a 20-gene expression signature was generated for differential diagnosis of PTC from BTN patients. Together, our work identified previously unreported molecular subtypes of PTC, offering opportunities to stratify patients into optimal treatment plans based on molecular subtyping.
Publisher: The Company of Biologists
Date: 2019
DOI: 10.1242/DMM.040147
Abstract: Human tumors exhibit plasticity and evolving capacity over time. It is difficult to study the mechanisms of how tumors change over time in human patients, in particular during the early stages when a few oncogenic cells are barely detectable. Here we used a Drosophila tumor model caused by loss of Scribble (Scrib), a highly conserved apicobasal cell polarity gene, to investigate the spatial-temporal dynamics of early tumorigenesis events. The fly scrib mutant tumors have been successfully used to model many aspects of tumorigenesis processes. However, it is still unknown whether the fly scrib mutant tumors exhibit plasticity and evolvability along the temporal axis. Here we first found that the scrib mutant tumors display different growth rates and cell cycle profiles over time, indicative of a growth arrest-to-proliferation transition as the scrib mutant tumors progress. Longitudinal bulk and single-cell transcriptomic analysis of the scrib mutant tumors revealed that the MAPK pathway, including the JNK and ERK signaling activities, shows quantitative changes over time. We found that high JNK signaling activity causes G2/M cell cycle arrest in the early scrib mutant tumors. In addition, JNK signaling activity displays a radial polarity with the JNKhigh cells located at the periphery of the scrib mutant tumors, providing an inherent mechanism that leads to an overall JNK signaling activity decrease over time. We also found that the ERK signaling activity, in contrast to JNK activity, increases over time and promotes growth in the late-stage scrib mutant tumors. Finally, high JNK signaling activity represses ERK signaling activity in the early scrib mutant tumors. Together, these data demonstrated that dynamic MAPK signaling activity, fueled by intratumor heterogeneity derived from tissue topological differences, drives a growth arrest-to-proliferation transition in the scrib mutant tumors.
Publisher: Rockefeller University Press
Date: 14-10-2013
DOI: 10.1084/JEM.20131448
Abstract: Richter syndrome (RS) derives from the rare transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly of the diffuse large B cell lymphoma (DLBCL) type. The molecular pathogenesis of RS is only partially understood. By combining whole-exome sequencing and copy-number analysis of 9 CLL-RS pairs and of an extended panel of 43 RS cases, we show that this aggressive disease typically arises from the predominant CLL clone by acquiring an average of ∼20 genetic lesions/case. RS lesions are heterogeneous in terms of load and spectrum among patients, and include those involved in CLL progression and chemorefractoriness (TP53 disruption and NOTCH1 activation) as well as some not previously implicated in CLL or RS pathogenesis. In particular, disruption of the CDKN2A/B cell cycle regulator is associated with ∼30% of RS cases. Finally, we report that the genomic landscape of RS is significantly different from that of de novo DLBCL, suggesting that they represent distinct disease entities. These results provide insights into RS pathogenesis, and identify dysregulated pathways of potential diagnostic and therapeutic relevance.
No related grants have been discovered for Jiguang Wang.