Hypermutation of <i>DPYD</i> Deregulates Pyrimidine Metabolism and Promotes Malignant Progression

Edwards, Lauren; Gupta, Rohit; Filipp, Fabian V.

doi:10.1158/1541-7786.mcr-15-0403

Cited by 29 publications

(26 citation statements)

References 24 publications

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“…Core modules within the PPI network of hypomethylation/high-expression genes possessed functions including the TGF-beta signaling pathway and pyrimidine metabolism, which affects DNA replication and the cell cycle in tumor cells. 28 Previous studies using profiling arrays have mostly analyzed either methylation or gene expression data, but not both. Furthermore, individual investigations have limited numbers of overlapping gene profiles and insufficient power to identify critical genes and pathways.…”

Section: Discussionmentioning

confidence: 99%

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer

Fan

et al. 2018

J of Cellular Biochemistry

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Aberrant methylation of DNA sequences plays a criticle role in finding novel aberrantly methylated genes and pathways in thyroid cancer (THCA). This study aimed to integrate three cohorts profile datasets to find novel aberrantly methylated genes and pathways in THCA. Data of gene expression profiling microarrays (GSE33630 and GSE65144) and gene methylation profiling microarrays (GSE51090) were downloaded from the Gene Expression Omnibus database. Aberrantly methylated and differentially expressed genes were sorted and pathways were analyzed. Functional and enrichment analyses of selected genes were performed using the String database. A protein‐protein interaction network was constructed using the Cytoscape software, and module analysis was performed using Molecular Complex detection. In total, we identified 12 hypomethylation/high‐expression genes and 30 hypermethylation/low‐expression genes at the screening step and, finally, found 6 mostly changed hub genes including PPARGC1A, CREBBP, EP300, CD44, SPP1, and MMP9. Pathway analysis showed that aberrantly methylated differentially expressed genes were mainly associated with the thyroid hormone signaling pathway, AMP‐activated protein kinase (AMPK) signaling pathway, and cell cycle process in THCA. After validation in the Cancer Genome Atlas database, the methylation and expression status of hub genes was significantly altered and the same with our results. Taken together, we identified novel aberrantly methylated genes and pathways in THCA, which could improve our understanding of the cause and underlying molecular events, and these candidate genes could serve as aberrant methylation‐based biomarkers for precise diagnosis and treatment of THCA.

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Section: Discussionmentioning

confidence: 99%

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer

Fan

et al. 2018

J of Cellular Biochemistry

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“…Edward et al (2016) showed a comprehensive view of how the polymorphisms in the DPYD gene deregulate the pyrimidine and nucleic acid synthesis, consequently, promoting malignant progression of melanoma [35]. A multicenter study concluded that variations in genes involved in the metabolism of pyrimidines, particularly the DPYD, may also influence the susceptibility to ovarian carcinoma [36].…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms of xenobiotic-metabolizing and transporter genes and the risk of gastric and colorectal cancer in an admixed population of Brazil.

Fernandes¹,

Castro²,

Carvalho³

et al. 2019

Preprint

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Introduction Colorectal (CRC) and Gastric (GC) cancers are responsible for considerable morbidity and mortality worldwide. In the North region of Brazil, these neoplasms are among the three most incident and aggressive types of cancer, constituting a severe problem of public health. Single Nucleotide Polymorphisms (SNPs) of xenobiotic metabolism and transporter genes may play a role in individual response to exposure to some of the compounds implicated in the cancer susceptibility. However, few studies have demonstrated the role of polymorphisms of xenobiotic metabolism and transporter genes in the susceptibility to CRC or GC in admixed populations. In this context, the study of variation in the activation and detoxification processes of xenobiotics may help to clarify the development of either GC or CRC in substructured populations, providing new insights about predictive diagnostic criteria in oncological investigations. MethodsWe performed an association study using 31 SNPs in 15 xenobiotic metabolism and transporter genes. The study was carried out in 121 CRC and 95 GC cases and 140 control individuals from Belém, a city which comprises a population with high levels of miscegenation, located in the Brazilian Amazon. Samples were genotyped using the QuantStudio™12K Flex Real-Time PCR System. Due to the high level of genetic admixture in the studied population, we applied a panel of 61 Ancestry Informative Marker standardized by our research group in an earlier study. Statistical analyses were performed in SPSS v.20.0 and Structure v.2.3.4ResultsThe results revealed a significant association between the increased CRC or GC risk and polymorphisms of ABCG2 (rs2231142) and DPYD genes (rs17116806, rs1801159). ConclusionsOur data suggest that polymorphisms in xenobiotic-metabolizing and transporter genes may be relevant to the susceptibility to both CRC and GC.

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“…A cancer systems biology analysis of skin cutaneous melanoma brought a new master regulator and diagnostic target in cancer metabolism forward. Somatic mutations of DPYD have the ability to reconfigure and activate pyrimidine metabolism promoting rapid cellular proliferation and metastatic progression [42].…”

Section: Discussionmentioning

confidence: 99%

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

Zecena

Tveit

Wang

et al. 2017

Preprint

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Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

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Hypermutation of DPYD Deregulates Pyrimidine Metabolism and Promotes Malignant Progression

Cited by 29 publications

References 24 publications

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer

Identification of candidate aberrantly methylated and differentially expressed genes in thyroid cancer

Polymorphisms of xenobiotic-metabolizing and transporter genes and the risk of gastric and colorectal cancer in an admixed population of Brazil.

Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

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