Identification of Molecular Subtypes of Gastric Cancer With Different Responses to PI3-Kinase Inhibitors and 5-Fluorouracil

Lei, Zhengdeng; Tan, Iain Beehuat; Das, Kakoli; Deng, Niantao; Zouridis, Hermioni; Pattison, Sharon; Chua, Clarinda; Zhu, Feng; Guan, Yeoh Khay; Ooi, Chia Huey; Ivanova, Tatiana; Zhang, Shenli; Lee, Ming‐Hui; Wu, Jeanie; Ngo, Anna; Manesh, Sravanthy; Tan, E.M.X.; Teh, Bin Tean; So, Jimmy Bok Yan; Goh, Liang Kee; Boussioutas, Alex; Lim, Tony Kiat Hon; Flotow, Horst; Tan, Patrick; Rozen, Steve

doi:10.1053/j.gastro.2013.05.010

Cited by 394 publications

(418 citation statements)

References 49 publications

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“…The cluster with aberrant p53 expression formed the majority of cases (51%), and is concordant with the chromosomal instability group (50%) of the Cancer Genome Atlas 6 , the proliferative subtype (45%) of Lei et al, 5 and the microsatellite-stable/ TP53 type of the Asian Cancer Research Group (35.7%). 7 A strong correlation with Lauren intestinal morphotype (81%) was seen, supporting this group's correspondence to chromosomal instability (84%) 6 , proliferative type (75%), 5 and microsatellite-stable/ TP53 type (85.1%).…”

Section: Discussionsupporting

confidence: 59%

“…[5][6][7] Hierarchical clustering resulted in the determination of the four main groups, and while these groups are not entirely mutually exclusive, an algorithm for their diagnostic distinction is provided (Figures 1 and 2). In our cohort, we found a lower incidence of EBV gastric cancers (5%) compared with the the Cancer Genome Atlas 6 (8.8%) and other publications (2-20%).…”

Section: Discussionmentioning

confidence: 99%

“…The 'Singapore-Duke' study identified three distinct molecular signatures based on genetic and epigenetic expression of drug-responsive clusters, and subclassified gastric adenocarcinoma into (a) a proliferative subtype characterized by high TP53 mutations and activation of oncogenic pathways, (b) a metabolic subtype with low TP53 mutations and expression of genes characteristic of normal gastric mucosa and metabolic pathways, among other features, and (c) a mesenchymal subtype with low expression of CDH1 and TP53, increased stem cell marker, and genes characteristic of the epithelial-mesenchymal transition pathway. 5 The authors commented that the proliferative and mesenchymal types corresponded to Lauren intestinal and diffuse types, respectively. Metabolic-type gastric cancers were highly sensitive to 5-fluorouracil, and the mesenchymal-type gastric adenocarcinomas were more sensitive to phosphatidyl-inositol-3-kinase inhibitors.…”

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confidence: 99%

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A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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“…Drug responses can be characterized by survival time, which is increased by effective treatment (Lei et al ., 2013; Pazdur, 2000; Zheng et al ., 2015). If DRCEs could be used to stratify prognosis, then that would mirror their potential drug response signatures.…”

Section: Resultsmentioning

confidence: 99%

“…Response to drug treatment is generally characterized by an increase in patient survival (Lei et al ., 2013; Pazdur, 2000; Zheng et al ., 2015). In this study, ceRNA associated with survival of patients treated with drug were considered to be DRCEs.…”

Section: Methodsmentioning

confidence: 99%

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

Zhang

Zhou

et al. 2018

Molecular Oncology

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Differences in individual drug responses are an obstacle to progression in cancer treatment, and predicting responses would help to plan treatment. The accumulation of cancer molecular profiling and drug response data provides opportunities and challenges to identify novel molecular signatures and mechanisms of tumor responsiveness to drugs. This study evaluated drug responses with a competing endogenous RNA (ceRNA) system that depended on competition between diverse RNA species. We identified drug response‐related ceRNA (DRCEs) by combining the sequence and expression data of long noncoding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA), and the survival data of cancer patients treated with drugs. We constructed a patient–drug two‐layer integrated network and used a linear weighting method to predict individual drug responses. DRCEs were found to be significantly enriched in known cancer and drug‐associated data resources, involved in biological processes known to mediate drug responses, and correlated to drug activity in cancer cell lines. The dysregulation of DRCE expression influenced drug response‐associated functions and pathways, suggesting DRCEs as potential therapeutic targets affecting drug responses. A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1‐related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations. In summary, this study provides a framework for ceRNA‐based evaluation of clinical drug responses across multiple cancer types. Understanding the underlying molecular mechanisms of drug responses will allow improved response to chemotherapy and outcomes of cancer treatment.

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FOXD1‐AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway

Wei

et al. 2020

Molecular Oncology

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Gastric cancer (GC) is a common gastrointestinal cancer with a high global mortality. Recent reports have suggested that long noncoding RNA (lncRNA) are implicated in multiple aspects of GC, including pathogenesis, progression, and therapeutic response. Herein, we investigated the function of FOXD1-AS1 in GC progression and chemoresistance. Expression of FOXD1-AS1 was low in normal stomach tissues but was upregulated in GC cell lines. Silencing of FOXD1-AS1 impaired GC cell proliferation and motility in vitro, and repressed tumor growth and metastasis in vivo. Importantly, FOXD1-AS1 upregulation increased the resistance of GC cells to cisplatin. Moreover, we found that FOXD1-AS1 promoted FOXD1 protein translation through the eIF4G-eIF4E-eIF4A translational complex. We also demonstrated that FOXD1-AS1 released eIF4E from phosphorylated 4E-BP1 and thereby strengthened the interaction of eIF4E with eIF4G by activating the PI3K/AKT/mTOR pathway. Activation of the PI3K/AKT/mTOR pathway was due to the post-transcriptional upregulation of PIK3CA, in turn induced by FOXD1-AS1-mediated sequestering of microRNA (miR)-466. Furthermore, we verified that FOXD1-AS1 facilitated GC progression and cisplatin resistance in a FOXD1-dependent manner. In conclusion, FOXD1-AS1 aggravates GC progression and chemoresistance by promoting FOXD1 translation via PIK3CA/PI3K/ AKT/mTOR signaling. These findings highlight a novel target for treatment of patients GC, particularly patients with cisplatin resistance.

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Identification of Molecular Subtypes of Gastric Cancer With Different Responses to PI3-Kinase Inhibitors and 5-Fluorouracil

Cited by 394 publications

References 49 publications

A protein and mRNA expression-based classification of gastric cancer

A protein and mRNA expression-based classification of gastric cancer

Inferences of individual drug responses across diverse cancer types using a novel competing endogenous RNA network

FOXD1‐AS1 regulates FOXD1 translation and promotes gastric cancer progression and chemoresistance by activating the PI3K/AKT/mTOR pathway

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