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Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

ABSTRACT: DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.

SUBMITTER: Linnekamp JF

PROVIDER: S-EPMC8153633 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

Linnekamp Janneke F JF Kandimalla Raju R Fessler Evelyn E de Jong Joan H JH Rodermond Hans M HM van Bochove Gregor G W GGW The Frans O FO Punt Cornelis J A CJA Bemelman Willem A WA van de Ven Anthony W H AWH Tanis Pieter J PJ Kemper Elles M EM Koens Lianne L Dekker Evelien E Vermeulen Louis L van Laarhoven Hanneke W M HWM Medema Jan Paul JP

Cancers 20210513 10

DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cance ...[more]

PMID: 34068407

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Project description:INTRODUCTION:Patients undergoing ileostomy surgery often experience electrolyte disturbances and dehydration, especially during the first post-operative period. Recently, research has also begun on how the newly constructed ileostomy affects the patient's nutritional status. AIM:The aim of the present pilot study was to assess the nutritional status of patients before and after the construction of the ileostomy as well as nutrition-related factors. MATERIAL AND METHOD:This was a pilot study. The sample consisted of 13 adult patients diagnosed with colorectal or colon cancer who underwent scheduled ileostomy surgery. The evaluation tool used was "Original Full Mini Nutritional Assessment (MNA)". Patients underwent nutritional assessment before the surgery (time 0), on the 7th post-operative day (time 1), and on the 20th post-operative day (time 2). The statistical significance level was set at p < 0.05. RESULTS:All patients had a drop in MNA score on the 7th and 20th post-operative days. Factors associated with MNA were weight loss, mobility, body mass index (BMI), number of full meals consumed per day, portions of fruits and vegetables consumed per day, and mid-arm circumference, p < 0.05, respectively. Pre-operatively, 38.5%, of patients had severe weight loss (>3 kg), 23% moderate weight loss and 38.5% minimal weight loss. Pre-operatively, 92.3% of participants were able to move on their own and 69.2% on the 20th post-operatively day. Furthermore, BMI >23 kg/m2 had 84.6% of participants pre-operatively and 30.8% on the 20th post-operative day. In terms of portions of fruits and vegetables consumed per day, 30.8% of patients consumed at least 2 times, pre-operatively and no one (0%) on the 20th post-operative day. Moreover, pre-operatively all participants (100%) had arm circumference >22 cm while on the 20th post-operative day, only 38.5% of participants had arm circumference >22 cm. CONCLUSIONS:In the first 20 days after the construction of an ileostomy, the nutritional status of the patients is significantly affected. Decreased patient nutrition in both quantity and ingredients and reduced fluid intake appear to adversely affect the patient's nutritional status.

Project description:Stage II colon cancer (CC) still remains a clinical challenge with patient stratification for adjuvant therapy (AT) largely relying on clinical parameters. Prognostic biomarkers are urgently needed for better stratification. Previously, we have shown that WNT target genes AXIN2, DKK1, APCDD1, ASCL2 and LGR5 are silenced by DNA methylation and could serve as prognostic markers in stage II CC patients using methylation-specific PCR. Here, we have extended our discovery cohort AMC90-AJCC-II (N=65) and methylation was analyzed by quantitative pyrosequencing. Subsequently, we validated the results in an independent EPICOLON1 CC cohort (N=79). Methylation of WNT target genes is negatively correlated to mRNA expression. A combination of AXIN2 and DKK1 methylation significantly predicted recurrences in univariate (area under the curve (AUC)=0.83, confidence interval (CI): 0.72-0.94, P<0.0001) analysis in stage II microsatellite stable (MSS) CC patients. This two marker combination showed an AUC of 0.80 (CI: 0.68-0.91, P<0.0001) in the EPICOLON1 validation cohort. Multivariate analysis in the Academic Medical Center (AMC) cohort revealed that both WNT target gene methylation and consensus molecular subtype 4 (CMS4) are significantly associated with poor recurrence-free survival (hazard ratio (HR)methylation: 3.84, 95% CI: 1.14-12.43; HRCMS4: 3.73, 95% CI: 1.22-11.48). CMS4 subtype tumors with WNT target methylation showed worse prognosis. Combining WNT target gene methylation and CMS4 subtype lead to an AUC of 0.89 (0.791-0.982, P<0.0001) for recurrence prediction. Notably, we observed that methylation of DKK1 is high in BRAF mutant and CIMP (CpG island methylator phenotype)-positive cancers, whereas AXIN2 methylation appears to be associated with CMS4. Methylation of AXIN2 and DKK1 were found to be robust markers for recurrence prediction in stage II MSS CC patients. Further validation of these findings in a randomized and prospective manner could pave a way to identify poor prognosis patients of stage II CC for AT.

Project description:BackgroundBoth pre-operative anemia and perioperative (intra- and/or post-operative) blood transfusion have been reported to increase post-operative complications in patients with colon cancer undergoing colectomy. However, their joint effect has not been investigated. The purpose of this study was to evaluate the joint effect of pre-operative anemia and perioperative blood transfusion on the post-operative outcome of colon-cancer patients after colectomy.MethodsWe identified patients from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database 2006-2016 who underwent colectomy for colon cancer. Multivariate logistic regression analysis was employed to assess the independent and joint effects of anemia and blood transfusion on patient outcomes.ResultsA total of 35,863 patients-18,936 (52.8%) with left-side colon cancer (LCC) and 16,927 (47.2%) with right-side colon cancer (RCC)-were identified. RCC patients were more likely to have mild anemia (62.7%) and severe anemia (2.9%) than LCC patients (40.2% mild anemia and 1.4% severe anemia). A total of 2,661 (7.4%) of all patients (1,079 [5.7%] with LCC and 1,582 [9.3%] with RCC) received a perioperative blood transfusion. Overall, the occurrence rates of complications were comparable between LCC and RCC patients (odds ratio [OR] = 1.01; 95% confidence interval [CI] = 0.95-1.07; P = 0.750). There were significant joint effects of anemia and transfusion on complications and the 30-day death rate (P for interaction: 0.010). Patients without anemia who received a transfusion had a higher risk of any complications (LCC, OR = 3.51; 95% CI = 2.55-4.85; P < 0.001; RCC, OR = 3.74; 95% CI = 2.50-5.59; P < 0.001), minor complications (LCC, OR = 2.54; 95% CI = 1.63-3.97; P < 0.001; RCC, OR = 2.27; 95% CI = 1.24-4.15; P = 0.008), and major complications (LCC, OR = 5.31; 95% CI = 3.68-7.64; P < 0.001; RCC, OR = 5.64; 95% CI = 3.61-8.79; P < 0.001), and had an increased 30-day death rate (LCC, OR = 6.97; 95% CI = 3.07-15.80; P < 0.001; RCC, OR = 4.91; 95% CI = 1.88-12.85; P = 0.001) than patients without anemia who did not receive a transfusion.ConclusionsPre-operative anemia and perioperative transfusion are associated with an increased risk of post-operative complications and increased death rate in colon-cancer patients undergoing colectomy.

Project description:Despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory. In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells. We demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells. However, the combination of the two compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line. The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway. In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration. Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor. Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone. Interestingly, combined treatment with these two drugs increased the expression of XIAP-associated factor 1 (XAF1) which play an important role in cell apoptosis. Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the two drugs. Our findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression. In conclusion, based on the observations from our study, we suggested that the combined administration of these two drugs might be considered as a novel therapeutic regimen for treating colon cancer.

Project description:BACKGROUND: The methylation inhibitor 5-Aza-2'-deoxycytidine (decitabine, DAC) has a great therapeutic value for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). But decitabine monotherapy was associated with a relatively low rate of complete remission in AML and MDS. We aimed to investigate the effect of several anti-leukemia drugs in combination with decitabine on the proliferation of myeloid leukemia cells, to select the most efficient combination group and explore the associated mechanisms of these combination therapies. METHODS: Cell proliferation was tested by MTT assay and CFU-GM assay. Cell apoptosis was evaluated by Annexin V and PI staining in cell culture, TUNEL assay and transmission electron microscopy in animal study. MicroPET was used to imaging the tumor in mouse model. Molecular studies were conducted using microarray expression analysis, which was used to explore associated pathways, and real-time quantitative reverse transcription-PCR, western blot and immunohistochemistry, used to assess regulation of Wnt/?-catenin pathway. Statistical significance among groups was determined by one-way ANOVA analysis followed by post hoc Bonferroni's multiple comparison test. RESULTS: Among five anti-leukemia agents in combining with decitabine, the sequential combination of decitabine and idarubicin induced synergistic cell death in U937 cells, and this effect was verified in HEL, SKM-1 cells and AML cells isolated from AML patients. Importantly, tumor growth inhibition in this sequential combination was found to be higher than in single agent or controls in vivo. Moreover, sequential combination of the two agents induced apoptosis and depression of the Wnt/?-catenin pathway in both AML cell culture and animal studies. CONCLUSIONS: The findings demonstrated that sequentially combination of decitabine and idarubicin had synergistic anti-leukemia effects. These effects were mainly attributed to demethylation of Wnt/?-catenin pathway inhibitors and downregulation of Wnt/?-catenin pathway nuclear targets.

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Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

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Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

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