Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers

Zhang, Yu An; Ma, Xiaotu; Sathe, Adwait Amod; Fujimoto, Junya; Wistuba, Ignacio I.; Lam, Stephen; Yatabe, Yasushi; Wang, Yi Wei; Stastny, Victor; Gao, Boning; Larsen, Jill E.; Girard, Luc; Liu, Xiaoyun; Song, Kai; Behrens, Carmen; Kalhor, Neda; Xie, Yang; Zhang, Michael Q.; Minna, John D.; Gazdar, Adi F.

doi:10.1016/j.jtho.2015.11.004

Cited by 11 publications

(13 citation statements)

References 53 publications

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“…A. Zhang et al, 2016). Reportedly, the expression of SCT is regulated by its methylation degree in the promoter region in human liver cancer and intestinal cancer cell lines (Lee, Tan-Un, Pang, Lam, & Chow, 2004a).…”

Section: Discussionmentioning

confidence: 99%

The overexpression of GRASP might inhibit cell proliferation and invasion in hepatocellular carcinoma

Cheng

Yin

Hou

et al. 2019

Journal Cellular Physiology

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This study aimed to validate the methylation of key genes in hepatocellular carcinoma (HCC) screened by bioinformatics analysis and explore whether they affected HCC cell proliferation, migration, and invasion. Using The Cancer Genome Atlas (TCGA) database, HCC‐related differentially methylated positions (DMPs) were screened, genes corresponding to DMPs were selected, and prognosis‐related genes were identified. A representative DMP was used to divide the DMPs into hyper‐ and hypomethylated groups. Expression of key genes in cell lines was detected using quantitative real‐time polymerase chain reaction and western blot analysis. After treatment of HepG2 cells with 5‐Aza‐2′‐deoxycytidine (5‐Aza‐DC), gene expression was observed. Bisulfite sequencing PCR assay was used to detect methylation frequency. Overexpressed GRASP lentiviral vectors were constructed to analyze their influence on cell proliferation, migration, and invasion using cell counting kit‐8 and transwell assays. Forty‐three HCC prognosis‐related genes were screened using the TCGA database. cg00249511 (SCT) was used to divide the DMPs into hyper‐ and hypomethylated groups, distinguishing between high‐ and low‐risk samples. The prognosis survival model constructed using 12 genes revealed the prognosis type. GRASP messenger RNA was downregulated in HepG2 and upregulated after 5‐Aza‐DC treatment. In HCC tissues, methylation frequency of GRASP was upregulated. GRASP overexpression inhibited HepG2 cell proliferation, invasion, and G‐CSFR expression. Thus, GRASP might be a prognosis‐related gene controlled by methylation.

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Section: Discussionmentioning

confidence: 99%

The overexpression of GRASP might inhibit cell proliferation and invasion in hepatocellular carcinoma

Cheng

Yin

Hou

et al. 2019

Journal Cellular Physiology

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“…Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma (Yang et al, 2013) and with poor survival in breast cancers (Hong et al, 2014). In our experience, some genes such as SCT and ITPKA , are frequently methylated in many invasive cancers, but their methylation in certain low-grade tumors is variable (Zhang et al, 2016, Wang et al, 2016). The availability of a well-studied large set of LGG having molecular data including exome sequencing and genome wide methylation (Cancer Genome Atlas Research et al, 2015), permitted us to examine the prognostic role of SHOX2 methylation and expression in gliomas and to correlate the data with other prognostic parameters.…”

Section: Introductionmentioning

confidence: 91%

SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas

et al. 2016

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BackgroundDiffuse gliomas, grades II and III, hereafter called lower-grade gliomas (LGG), have variable, difficult to predict clinical courses, resulting in multiple studies to identify prognostic biomarkers. The purpose of this study was to assess expression or methylation of the homeobox family gene SHOX2 as independent markers for LGG survival.MethodsWe downloaded publically available glioma datasets for gene expression and methylation. The Cancer Genome Atlas (TCGA) (LGG, n = 516) was used as a training set, and three other expression datasets (n = 308) and three other methylation datasets (n = 320), were used for validation. We performed Kaplan-Meier survival curves and univariate and multivariate Cox regression model analyses.FindingsSHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival. While they were tightly correlated, SHOX2 expression appeared more potent as a prognostic marker and was used for most further studies. The SHOX2 prognostic roles were maintained after analyses by histology subtypes or tumor grade. We found that the combination of SHOX2 expression and IDH genotype status identified a subset of LGG patients with IDH wild-type (IDHwt) and low SHOX2 expression with considerably favorable survival. We further investigated the combination of SHOX2 with other known clinically relevant markers of LGG (TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of LGG patients with significantly favorable survival outcomes, especially in the subgroup with worse prognosis for each individual marker. Finally, multivariate analysis demonstrated that SHOX2 was a potent independent survival marker.InterpretationWe have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. The combination of IDH or other relevant markers with SHOX2 identified LGG subsets with significantly different survival outcomes, and further understanding of these subsets may benefit therapeutic target identification and therapy selections for glioma patients.

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“…Although the functional implications of SCT promoter methylation remains to be defined, our study validated SCT promoter methylation as a biomarker for lung cancer. 36 In this study, we showed that the CpG island 2 in ITPKA gene body is highly methylated in lung cancer and ITPKA gene body methylation serves as a marker for early detection of lung cancer. Furthermore, we showed that ITPKA gene body methylation promotes its expression, facilitating the development of malignant phenotypes.…”

Section: Discussionmentioning

confidence: 67%

“…36 In the lung, SCT is expressed at an undetectable level in normal cells as well as in malignant cells regardless of its promoter methylation status. Although the functional implications of SCT promoter methylation remains to be defined, our study validated SCT promoter methylation as a biomarker for lung cancer.…”

Section: Discussionmentioning

confidence: 99%

ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers

Wang

Zhang

et al. 2016

Journal of Thoracic Oncology

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Introduction Despite recent advances in cancer therapy, the overall 5-year survival rate of patients with lung cancer remains low. The aim of our study was to search for novel markers for early diagnosis in patients with lung cancer. Methods Complementary DNA microarray analysis was performed in primary lung adenocarcinomas and cell lines to search for differentially expressed genes, followed by in vivo and in vitro tumorigenic assays to characterize the oncogenic potential of the candidate genes. Gene body methylation was analyzed by 450K methylation array, bisulfite sequencing, and quantitative methylation-specific polymerase chain reaction assays. In silico analysis of The Cancer Genome Atlas data set was also performed. Results Inositol-trisphosphate 3-kinase A gene (ITPKA), a kinase with limited tissue distribution, was identified as a potential oncogene. We showed that ITPKA expression is up-regulated in many forms of cancers, including lung and breast cancers, and that overexpressed ITPKA contributes to tumorigenesis. We also demonstrated that ITPKA expression is regulated by epigenetic DNA methylation of ITPKA gene body through modulation of the binding of SP1 transcription factor to the ITPKA promoter. ITPKA gene body displayed low or absent levels of methylation in most normal tissue but was significantly methylated in malignant tumors. In lung cancer, ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased after invasion. Conclusions ITPKA is a potential oncogene that it is overexpressed in most tumors, and its overexpression promotes tumorigenesis. ITPKA gene body methylation regulates its expression and thus serves as a novel and potential biomarker for early cancer detection.

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Validation of SCT Methylation as a Hallmark Biomarker for Lung Cancers

Cited by 11 publications

References 53 publications

The overexpression of GRASP might inhibit cell proliferation and invasion in hepatocellular carcinoma

The overexpression of GRASP might inhibit cell proliferation and invasion in hepatocellular carcinoma

SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II–III Diffuse Gliomas

ITPKA Gene Body Methylation Regulates Gene Expression and Serves as an Early Diagnostic Marker in Lung and Other Cancers

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