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Methylated DAPK and APC promoter DNA detection in peripheral blood is significantly associated with apparent residual tumor and outcome

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  • KMG Klinik Silbermühle GmbH

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Death-associated protein kinase (DAPK) and adenomatous polyposis coli gene (APC) have been recently shown to be associated with outcome in patients with esophageal carcinoma, especially adenocarcinoma. We wanted to validate the correlation of these two markers with outcome by detecting methylated DNA sequences in peripheral blood. Circulating cell-free DNA extracted from blood plasma of 59 patients with esophageal cancer was analyzed before and after surgical resection by quantitative real-time methylation-specific RT-PCR (TaqMan) assays. Thirty-six of 59 patients (61.0%) with esophageal cancer had detectable levels of methylated DAPK or APC promoter DNA and preoperative detection was significantly associated with an unfavorable prognosis as revealed by multivariate Cox proportional hazards regression analysis [Exp(b) = 4.578; P = 0.01]. The combination of both markers significantly increased sensitivity and specificity for discriminating between short (<2.5 years) and long survivors (P = 0.04, ROC curve analysis). Postoperative APC detection was significantly different if residual tumor was apparent (P = 0.03). Preoperative measurement of methylated DAPK and APC promoter DNA in peripheral blood may contribute to better estimate postoperative survival chances of patients with esophageal carcinoma, especially adenocarcinoma. The postoperative detection of methylated APC in peripheral blood might provide crucial information on apparent residual tumor and might be used as a "molecular" R0-Marker in addition to the pathologic examination.
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... The hypermethylation of APC promoter was also observed in the plasma of patients suggested as hypermethylation positive for tumor tissue (39,41,45). Researchers found that the detection rate of APC methylation was higher in the blood of patients who had undergone surgery but featured residual tumor than that of patients with radical resection (45). ...
... The hypermethylation of APC promoter was also observed in the plasma of patients suggested as hypermethylation positive for tumor tissue (39,41,45). Researchers found that the detection rate of APC methylation was higher in the blood of patients who had undergone surgery but featured residual tumor than that of patients with radical resection (45). Moreover, the hypermethylation level in the plasma increased with cancer stage (39,41,45). ...
... Researchers found that the detection rate of APC methylation was higher in the blood of patients who had undergone surgery but featured residual tumor than that of patients with radical resection (45). Moreover, the hypermethylation level in the plasma increased with cancer stage (39,41,45). For patients with recurrent lesions, it was found that whether they had been plasma DNA-methylated or not, methylated APC could be detected in their plasma. ...
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The adenomatous polyposis coli (APC) gene, known as tumor suppressor gene, has the two promoters 1A and 1B. Researches on APC have usually focused on its loss-of-function variants causing familial adenomatous polyposis. Hypermethylation, however, which is one of the key epigenetic alterations of the APC CpG sequence, is also associated with carcinogenesis in various cancers. Accumulating studies have successively explored the role of APC hypermethylation in gastrointestinal (GI) tumors, such as in esophageal, colorectal, gastric, pancreatic, and hepatic cancer. In sporadic colorectal cancer, the hypermethylation of CpG island in APC is even considered as one of the primary causative factors. In this review, we systematically summarized the distribution of APC gene methylation in various GI tumors, and attempted to provide an improved general understanding of DNA methylation in GI tumors. In addition, we included a robust overview of demethylating agents available for both basic and clinical researches. Finally, we elaborated our findings and perspectives on the overall situation of APC gene methylation in GI tumors, aiming to explore the potential research directions and clinical values.
... The prognostic value of assessing ctDNA levels has been wellestablished in detecting minimal residual disease following surgery in various cancer types including lung, colorectal, and bladder cancer, and is currently being explored in monitoring treatment responses of patients with advanced disease (13)(14)(15)(16)(17)(18)(19)(20). In addition, numerous reports have also demonstrated the detection of methylated ctDNA and its association to prognosis after surgery (21)(22)(23)(24)(25). The methylation status of genes such as APC, CDKN2A, RUNX3, RARB2, MSH2, and ESR1B in esophageal (22), liver (23), gastric (24), and breast cancer (25), respectively, has been associated with residual tumor after surgery and prognosis. ...
... In addition, numerous reports have also demonstrated the detection of methylated ctDNA and its association to prognosis after surgery (21)(22)(23)(24)(25). The methylation status of genes such as APC, CDKN2A, RUNX3, RARB2, MSH2, and ESR1B in esophageal (22), liver (23), gastric (24), and breast cancer (25), respectively, has been associated with residual tumor after surgery and prognosis. In addition to its potential as a prognostic marker, monitoring of methylated ctDNA can also predict response to therapy. ...
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e15535 Background: To improve the prognosis of resected lung cancer patients, growing efforts are being invested in finding the most optimal approach to detect MRD and predict relapse. In our study, we aimed to investigate the utility of ctDNA methylation profiling in detecting MRD from patients with resected early-stage NSCLC. Methods: Surgically-resected tumor tissues were obtained from 65 patients diagnosed with resectable stage IA-III NSCLC with various histological subtypes. Matched blood samples were also collected before surgery (baseline) and during regular follow-up after 2-8 weeks of surgery. Comprehensive somatic mutation and methylation level profile from circulating tumor DNA (ctDNA) were performed using unique molecular identifier-based targeted sequencing and targeted bisulfite sequencing, respectively. A tumor-informed MRD prediction model was constructed based on methylation levels obtained from the patient’s resected tumor tissue to calculate the corresponding methylation signal intensity from the matched plasma sample of the patient at baseline or other time points during follow-up, which is reflected as MRD score. Results: Of the 28 patients with baseline ctDNA methylation data, 28.6% (8/28) of the patients had elevated ctDNA methylation levels at first post-operative follow-up (F1) as compared to baseline, indicating the possibility of MRD. Meanwhile, of the 20 patients (71.4%, 20/28) who had reduced ctDNA methylation levels at F1, elevation of ctDNA methylation level was detected from 3 and 1 patients at second (F2) and third (F3) follow-up, respectively. Based on the MRD prediction model, 17.9% (5/28) of the patients had higher MRD scores at F1. Of the 23 patients with lower MRD scores at F1, 5, 1 and 1 patients had an elevation in MRD scores at F2, F3, and F4, respectively, which indicates a possible MRD. Disease relapse was radiologically confirmed after 10-16 months post-surgery in three patients with concomitant elevation of ctDNA methylation level and MRD score during follow-up between 2-9 months prior to radiologic relapse. Conclusions: Our results demonstrate that post-operative ctDNA methylation levels could be used to detect MRD in patients with resected NSCLC. Moreover, ctDNA methylation-based prediction model of MRD could serve as a potential model to predict relapse in early-stage as well as disease progression in advanced-stage NSCLC.
... The prognostic value of assessing ctDNA levels has been wellestablished in detecting minimal residual disease following surgery in various cancer types including lung, colorectal, and bladder cancer, and is currently being explored in monitoring treatment responses of patients with advanced disease (13)(14)(15)(16)(17)(18)(19)(20). In addition, numerous reports have also demonstrated the detection of methylated ctDNA and its association to prognosis after surgery (21)(22)(23)(24)(25). The methylation status of genes such as APC, CDKN2A, RUNX3, RARB2, MSH2, and ESR1B in esophageal (22), liver (23), gastric (24), and breast cancer (25), respectively, has been associated with residual tumor after surgery and prognosis. ...
... In addition, numerous reports have also demonstrated the detection of methylated ctDNA and its association to prognosis after surgery (21)(22)(23)(24)(25). The methylation status of genes such as APC, CDKN2A, RUNX3, RARB2, MSH2, and ESR1B in esophageal (22), liver (23), gastric (24), and breast cancer (25), respectively, has been associated with residual tumor after surgery and prognosis. In addition to its potential as a prognostic marker, monitoring of methylated ctDNA can also predict response to therapy. ...
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Background: Circulating tumor DNA (ctDNA) harboring tumor-specific genetic and epigenetic aberrations allows for early detection and real-time monitoring of tumor dynamics. In this study, we aimed to evaluate the potential of parallel serial assessment of somatic mutation and methylation profile in monitoring the response to osimertinib of epidermal growth factor receptor (EGFR) T790M-positive advanced lung adenocarcinoma patients. Methods: Parallel somatic mutation and DNA methylation profiling was performed on a total of 85 longitudinal plasma samples obtained from 8 stage IV osimertinib-treated EGFR T790M-positive lung adenocarcinoma patients. Results: Our results revealed a significant correlation between the by-patient methylation level with the maximum allele fraction (maxAF, P=0.0002). The methylation levels were significantly higher in the plasma samples of patients with detectable somatic mutations than patients without somatic mutations (P=0.0003) and healthy controls (P=0.0018). Moreover, analysis of both the DNA methylation level and maxAF revealed four trends of treatment response. Collectively, the decrease in methylation level and maxAF reflected treatment efficacy, while the gradual increase reflected impending disease progression (PD). Elevated methylation levels and maxAF were observed in 6 and 5 patients in an average lead-time of 3.0 and 1.9 months, respectively, prior to evaluation of PD using radiological imaging. Conclusions: DNA methylation profiling has the potential to predict disease relapse prior to evaluation through radiological modalities, suggesting that serial assessment of methylation level in combination with somatic mutation profiling are reliable methods for treatment monitoring. These methods should thus be incorporated with imaging modalities for a more comprehensive work-up of treatment response, particularly for patients treated with targeted therapies.
... Finally, 18 cohort studies met the inclusion and exclusion criteria and were included in our meta-analysis. [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] The basic characteristics of these studies were showed in Table 1. A total of 1,719 patients were involved in these studies, the median number of patients was 95, and the median CTC-positive patients rate of the patients was 44.3% (range from 13.9% to 69.4%). ...
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