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Objectives
Roughly half of hereditary nonpolyposis colorectal cancer (HNPCC) cases are Lynch syndrome and exhibit germ-line mutations in DNA mismatch repair (MMR) genes; the other half are familial colorectal cancer (CRC) type X (FCCTX) and are MMR proficient. About 70% of Lynch syndrome tumors have germ-line MLH1 or MSH2 mutations. The clinical pr...
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Context 1
... first included the DNA methylation data of all 194 CRC tumors resected from patients without a family history of CRC, for whom the microsatellite stability status was available from TCGA, and the DNA methylation data of the 32 matched normal tissues; these DNA methylation data were based on the HM27 BeadChip. 34 All data were downloaded on 30 January 2015 and will be referred to as the TCGA data set in this study (its characteristics are reported in Supplementary Table S1). The second data set consisted of DNA methylation data for 129 CRC tumors and 29 matched normal tissues from gene expression omnibus (GSE25062), as published by Hinoue et al. 33 The third data set consisted of 22 pairs of CRC tumors and adjacent normal tissues from gene expression omnibus (GSE17648), as published by Kim et al. 46 For the first and second data sets, we followed the method of Hinoue and colleagues to exclude 4,484 probes with a sequence that contained single-nucleotide polymorphisms or could not be uniquely aligned to the human genome, probes with a detection P value ≥ 0.05, and those located on chromosomes X and Y. 33 Because the DNA methylation data in the third data set did not provide detection P values and because the third data set consisted of Korean individuals, in subsequent analyses we used the same probes as those that were retained for the data set of HNPCC described above. ...
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... also followed the criteria of Hinoue et al. 33 to classify 36 tumors as CIMP-H, CIMP-L, or non-CIMP tumors; the details of these criteria are provided in Supplementary Table S2. The clinical and genetic features of these 36 tumors are given in Table 1. In this study, patients with MSS HNPCC were analyzed to identify diagnostic DNA methylation gene-marker panels. ...
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... the probe cg00893636, we found three MSI hMLH1 tumors in the TCGA data set (see column B and row 19 in Supplementary Table S1). Thus, we identified 29 "sporadic MSS CRC" tumors. ...
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... followed the practice in this area to consider panels with five markers. In fact, there were 18 sets of five-marker panels with 100% sensitivity and 490% specificity in the discovery and validation cohorts (see Supplementary Table S10 online for a list of these sets). Specifically, among these 18 sets, another two sets had not only the same specificity (93.2%) as the original mark panel but the same DNA methylation profiles in the two patients indicated by the two blue arrows in Figure 2c as the original mark panel (data not shown). ...
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Background
Lynch syndrome (LS) due to an inherited damaging mutation in mismatch repair (MMR) genes comprises 3% of all incident colorectal cancer (CRC). Molecular testing using immunohistochemistry (IHC) for MMR proteins is a recommended screening tool to identify LS in incident CRC. This study assessed outcomes of population-based routine molecul...
Citations
... Unlike the well-established germline pathogenic variants in MMR which help identify the syndrome, much less is known about acquired molecular alterations in precursor colorectal neoplasms which might serve as early detection markers for screening and surveillance. However, several studies have demonstrated differences in the profiles of acquired genetic and epigenetic changes in colorectal neoplasms between LS and sporadic patients [21][22][23][24]. ...
... These novel MDMs that we found to be highly discriminant in tissue have potential for application as a novel screening modality that can complement colonoscopy to optimize early detection of colorectal neoplasia in LS. While some have used chip-based and other discovery methods to evaluate methylation differences in LS compared with sporadic colorectal neoplasms [21][22][23][24], to our knowledge, this is the first study to identify candidate MDMs for detection of LS colorectal neoplasms through discovery by unbiased next-generation methylation sequencing followed by independent tissue validation. All MDM candidates in our study were intentionally selected to represent aberrantly hyper-methylated sequences, as neoplasia-associated hypomethylation is a more subtle effect relative to the normal state and thus more difficult to measure in distant media. ...
... Epigenomics (2020) 12(24) future science group ...
Aim
Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients.
Patients & methods
For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls.
Results
OPLAH was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. ALKBH5, was uniquely hypermethylated in LS neoplasms.
Conclusion
Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.
... To date, great attention has been paid to investigate the relationship between methylation-driven genes (MDGs) and tumorigenesis (Pu et al., 2017). Recent studies have proved that MDGs participates in various lethal diseases like lung adenocarcinoma (Gao et al., 2018), pancreatic cancer , renal carcinoma Wang et al., 2020), and colon cancer (Chen et al., 2016). Meanwhile, many studies revealed that numerous genes are abnormally hypermethylated or hypomethylated in HCC (Hlady et al., 2019). ...
Although great progress has been made in treatment against hepatitis virus infection, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfied. Therefore, there is an unmet need to explore biomarkers or prognostic models for monitoring non-viral hepatocellular carcinoma. Accumulating evidence indicates that DNA methylation participates in carcinogenesis of malignancies. In the present study, we analyzed 101 non-viral HCC patients from TCGA database to figure out methylation-driven genes (MDGs) that might get involved in non-viral HCC pathogenesis using MethyMix algorithm. Then we picked out 8 key genes out of 137 MDGs that could affect the overall survival (OS) of both methylation and expression level. Using PCA, Uni-variate, Multi-variate, and LASSO cox regression analyses, we confirmed the potential prognostic value of these eight epigenetic genes. Ultimately, combined with immunohistochemistry (IHC), ROC, OS, and GSEA analyses, fat storage-inducing transmembrane protein1 (FITM1) was identified as a novel tumor suppressor gene in non-viral HCC and an applicable FITM1-methylation-based signature was built in a training set and validated in a testing set. Briefly, our work provides several potential biomarkers, especially FITM1, as well as a new method for disease surveillance and treatment strategy development.
... RASL10B encodes a small GTPase with antitumor properties, and epigenetic silencing of this gene has been attributed to hepatocellular carcinoma cells and breast cancer [78,79]. RASL10B has been reported to be differentially hypomethylated in FXXC cancers compared to Lynch syndrome cancers [80]. RASL10B is one member of Ras superfamily with antitumor potential. ...
Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation.
... ZNF542 (zinc finger protein 542) is a pseudogene, which also may be involved in transcriptional regulation. Studies have found hyper-methylation of ZNF542 in oropharyngeal squamous cell carcinoma and sporadic colorectal cancer [37,38]. Moreover, a pan-cancer study analysis based on the TCGA methylation datasets identified the hyper-methylation status of ZNF542 in 12 cancer types [39]. ...
Background
DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. However, limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC).
Methods
A high-throughput DNA methylation dataset (100 samples) of ESCC from The Cancer Genome Atlas (TCGA) project was analyzed and validated along with another independent dataset (12 samples) from the Gene Expression Omnibus (GEO) database. The methylation status of peripheral blood mononuclear cells and peripheral blood leukocytes from healthy controls was also utilized for biomarker selection. The candidate CpG sites as well as their adjacent regions were further validated in 94 pairs of ESCC tumor and adjacent normal tissues from the Chinese Han population using the targeted bisulfite sequencing method. Logistic regression and several machine learning methods were applied for evaluation of the diagnostic ability of our panel.
Results
In the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 × 10⁻⁴; cg19396867, P = 3.60 × 10⁻⁴; cg20655070, P = 3.60 × 10⁻⁴; cg26671652, P = 5.77 × 10⁻⁴; and cg27062795, P = 3.60 × 10⁻⁴. In the validation stage, the methylation status of both the five CpG sites and their adjacent genomic regions were tested. The diagnostic model based on the combination of these five genomic regions yielded a robust performance (sensitivity = 0.75, specificity = 0.88, AUC = 0.85). Eight statistical models along with five-fold cross-validation were further applied, in which the SVM model reached the best accuracy in both training and test dataset (accuracy = 0.82 and 0.80, respectively). In addition, subgroup analyses revealed a significant difference in diagnostic performance between the alcohol use and non-alcohol use subgroups.
Conclusions
Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.
Electronic supplementary material
The online version of this article (10.1186/s13148-017-0430-7) contains supplementary material, which is available to authorized users.
