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      Circulating methylated Septin 9 and ring finger protein 180 for noninvasive diagnosis of early gastric cancer

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          Abstract

          Background

          Gastric cancer (GC) has a poor prognosis due to patients often being diagnosed at an advanced stage, when metastasis has already occurred. To improve the 5-year survival rate and reduce the number of cancer-related deaths in patients with GC, noninvasive methods for early detection need to be developed. This study aimed to evaluate the value of circulating methylated Septin 9 ( SEPT9) and ring finger protein 180 ( RNF180) for the early diagnosis of GC.

          Methods

          Seventy-four patients with early GC, 99 patients with benign gastric diseases (BGD) (inflammation, polyps, intestinal metaplasia, ulcers, and erosion), and 57 cases with no evidence of disease (NED) were enrolled. Methylated SEPT9 and RNF180 in circulating cell-free DNA in blood samples from each group were detected, and the positivity rates were calculated. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), confidence interval (CI), and area under the curve (AUC) were determined for methylated SEPT9 and RNF180 in relation to early GC.

          Results

          As a diagnostic target, methylated SEPT9 had a sensitivity of 28.3% (95% CI: 18.5–40.0%), specificity of 94.2% (95% CI: 89.3–97.3%), and AUC value of 0.616 (95% CI: 52.0–71.1%). Methylated RNF180 had a sensitivity of 32.4% (95% CI: 22.0–44.3%), specificity of 89.7% (95% CI: 83.9–94.0%), and AUC value of 0.636 (95% CI: 54.2–73.0%). A combination of the two yielded a sensitivity of 40.5% (95% CI: 29.3–52.6%), specificity of 85.3% (95% CI: 78.7–90.4%), and AUC value of 0.65 (95% CI: 55.7–74.4%).

          Conclusions

          Methylated SEPT9 and RNF180 could be used as diagnostic biomarkers for early gastric cancer (EGC).

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          Most cited references33

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            DNA methylation and its basic function.

            In the mammalian genome, DNA methylation is an epigenetic mechanism involving the transfer of a methyl group onto the C5 position of the cytosine to form 5-methylcytosine. DNA methylation regulates gene expression by recruiting proteins involved in gene repression or by inhibiting the binding of transcription factor(s) to DNA. During development, the pattern of DNA methylation in the genome changes as a result of a dynamic process involving both de novo DNA methylation and demethylation. As a consequence, differentiated cells develop a stable and unique DNA methylation pattern that regulates tissue-specific gene transcription. In this chapter, we will review the process of DNA methylation and demethylation in the nervous system. We will describe the DNA (de)methylation machinery and its association with other epigenetic mechanisms such as histone modifications and noncoding RNAs. Intriguingly, postmitotic neurons still express DNA methyltransferases and components involved in DNA demethylation. Moreover, neuronal activity can modulate their pattern of DNA methylation in response to physiological and environmental stimuli. The precise regulation of DNA methylation is essential for normal cognitive function. Indeed, when DNA methylation is altered as a result of developmental mutations or environmental risk factors, such as drug exposure and neural injury, mental impairment is a common side effect. The investigation into DNA methylation continues to show a rich and complex picture about epigenetic gene regulation in the central nervous system and provides possible therapeutic targets for the treatment of neuropsychiatric disorders.
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              Recent advances in gastric cancer early diagnosis

              Gastric cancer (GC) remains an important cause of cancer death worldwide with a high mortality rate due to the fact that the majority of GC cases are diagnosed at an advanced stage when the prognosis is poor and the treatment options are limited. Unfortunately, the existing circulating biomarkers for GC diagnosis and prognosis display low sensitivity and specificity and the GC diagnosis is based only on the invasive procedures such as upper digestive endoscopy. There is a huge need for less invasive or non-invasive tests but also highly specific biomarkers in case of GC. Body fluids such as peripheral blood, urine or saliva, stomach wash/gastric juice could be a source of specific biomarkers, providing important data for screening and diagnosis in GC. This review summarized the recently discovered circulating molecules such as microRNAs, long non-coding RNAs, circular RNAs, which hold the promise to develop new strategies for early diagnosis of GC.
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                Author and article information

                Journal
                Transl Cancer Res
                Transl Cancer Res
                TCR
                Translational Cancer Research
                AME Publishing Company
                2218-676X
                2219-6803
                November 2020
                November 2020
                : 9
                : 11
                : 7012-7021
                Affiliations
                [1]Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research , deptMinistry of Education , Beijing, China
                Author notes

                Contributions: (I) Conception and design: All authors; (II) Administrative support: Q Wu; (III) Provision of study materials or participants: CQ Cao, L Chang; (IV) Collection and assembly of data: CQ Cao, L Chang; (V) Data analysis and interpretation: CQ Cao, L Chang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

                [#]

                These authors contributed equally to this work.

                Correspondence to: Qi Wu. Department of Endoscopy Center, Peking University Cancer Hospital & Institute, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Beijing 100142, China. Email: wuqi1973@ 123456163.com .
                Article
                tcr-09-11-7012
                10.21037/tcr-20-1330
                8799148
                35117307
                04b49798-0c08-49d3-9e61-1e81f745f31b
                2020 Translational Cancer Research. All rights reserved.

                Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

                History
                : 04 March 2020
                : 28 September 2020
                Funding
                Funded by: the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support
                Award ID: ZYLX201701
                Categories
                Original Article

                early gastric cancer (egc),diagnostic biomarker,methylation,septin 9 (sept9),ring finger protein 180 (rnf180)

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