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Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer.

ABSTRACT: Identification of early-stage tumor and monitoring therapeutic efficacy and recurrence or metastasis of colorectal cancer (CRC) are urgently warranted for improving the outcome of CRC patients and reducing the disease-related mortality. In this study, we evaluated the diagnostic value of cell-free circulating methylated SEPT9 (mSEPT9) for CRC and beyond CRC and examined the potentiality of mSEPT9 in assessing therapeutic efficacy and monitoring recurrence of CRC. Our results confirmed the favorable diagnostic value of plasma mSEPT9 for CRC, with a sensitivity of 61.22% (95% confidence interval (CI): 51.33%-70.27%) and specificity of 93.7% (95% CI: 91.09%-95.57%) using 2/3 algorithm. The positive rate of mSEPT9 in CRC was correlated with tumor size, histological grade, and general histological type (P < 0.05). Beyond CRC, gastric cancer patients also presented a high positive rate of plasma mSEPT9 (70%). The conversions between preoperative and postoperative plasma mSEPT9 reflected the therapeutic efficacy of curatively intended surgery for CRC patients. The persistent positivity of plasma mSEPT9 after surgery (within 7-14?days) was highly associated with impending recurrences or metastases (within one year), with a sensitivity of 100%. Postoperative mSEPT9 status during follow-up also provided valuable indication for CRC recurrence or metastases, with a good consistency (kappa?=?0.818, P = 0.001). Our results verified the reliability of plasma mSEPT9 as a biomarker for noninvasive diagnosis of CRC. More significantly, we revealed its valuable role in appraising CRC therapeutic efficacy and monitoring CRC recurrences or metastases. Further studies with larger sample sizes are needed to verify and elucidate the clinical utility of the promising findings.

SUBMITTER: Fu B

PROVIDER: S-EPMC5937566 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer.

Fu Bo B Yan Peng P Zhang Shan S Lu Yan Y Pan Li L Tang Wenqiang W Chen Shen S Chen Shuangfeng S Zhang Anqi A Liu Wei W

Disease markers 20180423

Identification of early-stage tumor and monitoring therapeutic efficacy and recurrence or metastasis of colorectal cancer (CRC) are urgently warranted for improving the outcome of CRC patients and reducing the disease-related mortality. In this study, we evaluated the diagnostic value of cell-free circulating methylated SEPT9 (mSEPT9) for CRC and beyond CRC and examined the potentiality of mSEPT9 in assessing therapeutic efficacy and monitoring recurrence of CRC. Our results confirmed the favora ...[more]

PMID: 29849824

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Project description:BACKGROUND: Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients. Methylation of the genes helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker. However the underlying mechanisms leading to the release of these genes are unclear. This study aimed at examining the possible correlation of the presence of methylated genes NEUROG1, HLTF and HPP1 in serum with tissue breakdown as a possible mechanism using serum lactate dehydrogenase (LDH) as a surrogate marker. Additionally the prognostic impact of these markers was examined. METHODS: Pretherapeutic serum samples from 259 patients from all cancer stages were analyzed. Presence of hypermethylation of the genes HLTF, HPP1, and NEUROG1 was examined using methylation-specific quantitative PCR (MethyLight). LDH was determined using an UV kinetic test. RESULTS: Hypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively). Also, higher LDH values correlated with a higher percentage of a fully methylated reference in a linear fashion (Spearman correlation coefficient 0.18 for HLTF [p = 0.004]; 0.49 [p < .0001] for HPP1). No correlation between methylation of NEUROG1 and LDH was found in this study. Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC. Accordingly, these three markers were correlated with significantly shorter survival in the overall population. Moreover, all three identified patients with a worse prognosis in the subgroup of stage IV patients. CONCLUSIONS: We were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker. Additionally, we found that prognostic information is given by both HLTF and HPP1 as well as LDH. In sum, determining the methylation of HLTF and HPP1 in serum might be useful in order to identify patients with more aggressive tumors.

Project description:BackgroundAs a crucial epigenetic modification, DNA 5-hydroxymethylcytosine (5-hmC) plays a key role during colorectal cancer (CRC) carcinogenesis. Nevertheless, the levels of 5-hmC-related genes in the circulating DNA of CRC remain largely unknown.Methods and resultsThe GSE81314 dataset from the Gene Expression Omnibus (GEO), which was generated by chemical marking-based low-input shotgun sequencing to detect 5-hmC in circulating cell-free DNA (cfDNA) was used in the present study. The GSE81314 dataset includes data for 8 plasma samples from healthy individuals and 4 plasma samples from CRC patients. The difference in the 5-hmC levels in cfDNA between the CRC group and healthy individuals was analyzed by the differentially expressed genes (DEG) package. Weighted gene coexpression network analysis (WGCNA) was conducted to analyze gene coexpression modules associated with sample characteristics. DEG analysis identified 19 upregulated and 9 downregulated 5-hmC-related genes. WGCNA showed that the pink, purple, and brown modules, which contain 531 genes in total, were significantly correlated with CRC (0.66, 0.61, and -0.59, respectively). We used gene set enrichment analysis (GSEA) software to compare 5-hmC-related genes and pathways between CRC patients and healthy controls. We further performed a protein-protein interaction (PPI) analysis and identified 4 nodes (LCN2, LRG1, S100P, and TACSTD2) that played key roles in the network, and we analyzed the expression of these nodes S100P in the GEPIA database. Consistent with the 5-hmC levels in CRC patient plasma, our external validation results from the GEPIA and UALCAN databases showed that LCN2, LRG1, S100P, and TACSTD2 were highly expressed in CRC tissue compared with controls. The DNA promoter methylation levels of LCN2, LRG1, and S100P were lower in CRC tissue than in normal control tissue.ConclusionThe present findings suggest that abnormality in cell-free DNA hydroxylation in plasma may be associated with CRC. In addition, the 5-hmC levels of LCN2, LRG1, S100P, and TACSTD2 in circulating cfDNA may be used as potential noninvasive markers for CRC.

Dataset Information

Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer.

Publications

Cell-Free Circulating Methylated SEPT9 for Noninvasive Diagnosis and Monitoring of Colorectal Cancer.

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