Patrick Kwok‐Shing Ng

UConn Health

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Gordon B. Mills

Oregon Health & Science University

Kenneth L. Scott

Baylor College of Medicine

Funda Meric‐Bernstam

The University of Texas MD Anderson Cancer Center

Stephen Kwok‐Wing Tsui

Chinese University of Hong Kong

Kang Jin Jeong

Oregon Health & Science University

Nidhi Sahni

The University of Texas MD Anderson Cancer Center

Carman K. M. Ip

University of Chicago

P. Andrew Futreal

The University of Texas MD Anderson Cancer Center

Xingzhi Song

The University of Texas MD Anderson Cancer Center

Zhenlin Ju

Jilin Agricultural Science and Technology University

Cooperative Institutions

The University of Texas MD Anderson Cancer Center

Harvard University

The University of Texas Health Science Center at Houston

Brigham and Women's Hospital

Baylor College of Medicine

University of Pittsburgh

Chinese University of Hong Kong

Dana-Farber Cancer Institute

University of Hong Kong

National Institutes of Health

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Transcriptome analysis of different developmental stages of amphioxus reveals dynamic changes of distinct classes of genes during development

Scientific Reports (2016)

Kevin Y. Yang Yuan Chen Zuming Zhang Patrick Kwok‐Shing Ng Wayne Jun-Wei Zhou

Abstract Vertebrates diverged from other chordates approximately 500 million years ago and have adopted several modifications of developmental processes. Amphioxus is widely used in evolutionary developmental biology research, such as on the basic patterning mechanisms involved in the chordate body plan and the origin of vertebrates. The fast development of next-generation sequencing has advanced knowledge of the genomic organization of amphioxus; however, many aspects of gene regulation during amphioxus development have not been fully characterized. In this study, we applied high-throughput sequencing on the transcriptomes of 13 developmental stages of Chinese amphioxus to gain a comprehensive understanding of transcriptional processes occurring from the fertilized egg to the adult stage. The expression levels of 3,423 genes were significantly changed (FDR ≤ 0.01). All of these genes were included in a clustering analysis and enrichment of biological functions associated with these clusters was determined. Significant changes were observed in several important processes, including the down-regulation of the cell cycle and the up-regulation of translation. These results should build a foundation for identifying developmentally important genes, especially those regulatory factors involved in amphioxus development and advance understanding of the developmental dynamics in vertebrates.

Body plan

Chordate

Developmental Biology

Evolutionary developmental biology

Gene regulatory network

10.1038/srep23195

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Citations (18)

Characterization of a hypoxia-responsive leptin receptor (omLepRL) cDNA from the marine medaka (Oryzias melastigma)

Marine Pollution Bulletin (2007)

Minnie Man Lai Wong Richard Man Kit Yu Patrick Kwok‐Shing Ng Sheran H.W. Law Alex Tsang

Hypoxia

Oryzias

10.1016/j.marpolbul.2007.01.025

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Citations (49)

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

Proceedings of the National Academy of Sciences (2014)

Vivian Wai Yan Lui Noah D. Peyser Patrick Kwok‐Shing Ng Jozef Hritz Yan Zeng

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a "driver" phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine-substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.

Hyperphosphorylation

Mutant protein

10.1073/pnas.1319551111

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Citations (98)

Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies

Nature Communications (2018)

Carman K. M. Ip Patrick Kwok‐Shing Ng Kang Jin Jeong Shan Shao Zhenlin Ju

Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.

PDGFRA

Targeted Therapy

10.1038/s41467-018-06949-w

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Citations (63)

Efficacy of futibatinib, an irreversible fibroblast growth factor receptor inhibitor, in FGFR-altered breast cancer

Scientific Reports (2023)

Turçin Saridogan Argun Akçakanat Ming Zhao Kurt W. Evans Erkan Yuca

Abstract Several alterations in fibroblast growth factor receptor (FGFR) genes have been found in breast cancer; however, they have not been well characterized as therapeutic targets. Futibatinib (TAS-120; Taiho) is a novel, selective, pan-FGFR inhibitor that inhibits FGFR1-4 at nanomolar concentrations. We sought to determine futibatinib’s efficacy in breast cancer models. Nine breast cancer patient–derived xenografts (PDXs) with various FGFR1-4 alterations and expression levels were treated with futibatinib. Antitumor efficacy was evaluated by change in tumor volume and time to tumor doubling. Alterations indicating sensitization to futibatinib in vivo were further characterized in vitro . FGFR gene expression between patient tumors and matching PDXs was significantly correlated; however, overall PDXs had higher FGFR3-4 expression. Futibatinib inhibited tumor growth in 3 of 9 PDXs, with tumor stabilization in an FGFR2 -amplified model and prolonged regression (> 110 days) in an FGFR2 Y375C mutant/amplified model. FGFR2 overexpression and, to a greater extent, FGFR2 Y375C expression in MCF10A cells enhanced cell growth and sensitivity to futibatinib. Per institutional and public databases, FGFR2 mutations and amplifications had a population frequency of 1.1%–2.6% and 1.5%–2.5%, respectively, in breast cancer patients. FGFR2 alterations in breast cancer may represent infrequent but highly promising targets for futibatinib.

10.1038/s41598-023-46586-y

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Citations (9)

A functional genomic approach to actionable gene fusions for precision oncology

Science Advances (2022)

Jun Li Hengyu Lu Patrick Kwok‐Shing Ng Angeliki Pantazi Carman K. M. Ip

Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.

10.1126/sciadv.abm2382

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Citations (19)

Spatially resolved analyses link genomic and immune diversity and reveal unfavorable neutrophil activation in melanoma

Nature Communications (2020)

Akash Mitra Miles C. Andrews Whijae Roh Mariana Petaccia de Macêdo Courtney W. Hudgens

Complex tumor microenvironmental (TME) features influence the outcome of cancer immunotherapy (IO). Here we perform immunogenomic analyses on 67 intratumor sub-regions of a PD-1 inhibitor-resistant melanoma tumor and 2 additional metastases arising over 8 years, to characterize TME interactions. We identify spatially distinct evolution of copy number alterations influencing local immune composition. Sub-regions with chromosome 7 gain display a relative lack of leukocyte infiltrate but evidence of neutrophil activation, recapitulated in The Cancer Genome Atlas (TCGA) samples, and associated with lack of response to IO across three clinical cohorts. Whether neutrophil activation represents cause or consequence of local tumor necrosis requires further study. Analyses of T-cell clonotypes reveal the presence of recurrent priming events manifesting in a dominant T-cell clonotype over many years. Our findings highlight the links between marked levels of genomic and immune heterogeneity within the physical space of a tumor, with implications for biomarker evaluation and immunotherapy response.

Cancer Immunotherapy

Priming (agriculture)

10.1038/s41467-020-15538-9

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Citations (19)

Cancer driver mutation prediction through Bayesian integration of multi-omic data

PLoS ONE (2018)

Zixing Wang Patrick Kwok‐Shing Ng Tenghui Chen Tae-Beom Kim Fang Wang

Identification of cancer driver mutations is critical for advancing cancer research and personalized medicine. Due to inter-tumor genetic heterogeneity, many driver mutations occur at low frequencies, which make it challenging to distinguish them from passenger mutations. Here, we show that a novel Bayesian hierarchical modeling approach, named rDriver can achieve enhanced prediction accuracy by identifying mutations that not only have high functional impact scores but also are associated with systemic variation in gene expression levels. In examining 3,080 tumor samples from 8 cancer types in The Cancer Genome Atlas, rDriver predicted 1,389 driver mutations. Compared with existing tools, rDriver identified more low frequency mutations associated with lineage specific functional properties, timing of occurrence and patient survival. Evaluation of rDriver predictions using engineered cell-line models resulted in a positive predictive value of 0.94 in PIK3CA genes. Our study highlights the importance of integrating multi-omic data in predicting cancer driver mutations and provides a statistically rigorous solution for cancer target discovery and development.

Personalized Medicine

10.1371/journal.pone.0196939

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Citations (23)

Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases

Proceedings of the National Academy of Sciences (2021)

Xinran Li Amy Yuet Ting Lau Angel S.N. Ng Abdullah Aldehaiman Yuan Zhou

Significance Phosphoinositide 3-kinase activation typically occurs following stimulation by upstream receptor tyrosine kinases (RTKs), which alleviate p110α inhibition by p85α. p85α and p110α driver mutations have been reported to activate p110α by disrupting the inhibitory interface between p85α and p110α. This study revealed that driver mutations in the p85α N-terminal SH2 domain can enhance p110α activity by inducing the activation of multiple RTKs. Furthermore, combination treatment with RTK and AKT inhibitors provides synergistic therapeutic efficacy. This previously uncharacterized oncogenic mechanism presents the exploitable vulnerability of a class of p85α mutant tumors.

P110α

Protein kinase domain

10.1073/pnas.2101751118

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Citations (12)

The G1613A Mutation in the HBV Genome Affects HBeAg Expression and Viral Replication through Altered Core Promoter Activity

PLoS ONE (2011)

Man-Shan Li Terrence Chi‐Kong Lau Sophie Ka-Ping Chan Chi Hang Wong Patrick Kwok‐Shing Ng

Infection of hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we demonstrated that the G1613A mutation in the HBV negative regulatory element (NRE) is a hotspot mutation in HCC patients. In this study, we further investigated the functional consequences of this mutation in the context of the full length HBV genome and its replication. We showed that the G1613A mutation significantly suppresses the secretion of e antigen (HBeAg) and enhances the synthesis of viral DNA, which is in consistence to our clinical result that the G1613A mutation associates with high viral load in chronic HBV carriers. To further investigate the molecular mechanism of the mutation, we performed the electrophoretic mobility shift assay with the recombinant RFX1 protein, a trans-activator that was shown to interact with the NRE of HBV. Intriguingly, RFX1 binds to the G1613A mutant with higher affinity than the wild-type sequence, indicating that the mutation possesses the trans-activating effect to the core promoter via NRE. The trans-activating effect was further validated by the enhancement of the core promoter activity after overexpression of RFX1 in liver cell line. In summary, our results suggest the functional consequences of the hotspot G1613A mutation found in HBV. We also provide a possible molecular mechanism of this hotspot mutation to the increased viral load of HBV carriers, which increases the risk to HCC.

HBeAg

10.1371/journal.pone.0021856

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Citations (27)