Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

Hypermethylation of SHISA3 DNA as a blood-based biomarker for colorectal cancer.

In Taiwan, colorectal cancer (CRC) is the second most common cancer and the cancer with the third highest mortality rate. This may be because of the difficulty of detecting the disease in the early stages, as well as the fact that colonoscopy, a typical method used in screening for CRC, causes discomfort to the recipient and is prone to technical interference. For the earlier detection of CRC, finding an easier screening method with a simpler collection procedure is essential. Thus, in the present study, plasma samples from patients with CRC were analyzed to determine the extent of methylation in SHISA3 DNA. Studies have suggested that SHISA3, a newly identified tumor suppressor, can regulate tumor growth, and that the inactivation of its DNA can be traced to epigenomic alterations in CRC. Another study reported the presence of hypermethylated SHISA3 DNA in CRC biopsy specimens. In the present study, the plasma of 30 patients with CRC and nine healthy controls was collected and analyzed for the concentration of cell-free DNA through bisulfite sequencing. The methylation rates were determined. Our results have shown that an increasing amount of cell-free DNA in the group of CRC patient's plasma compared to the healthy group. Moreover, patients with later stages of CRC had higher concentrations of cell-free DNA. Notably, the methylation rate of SHISA3 was higher in the plasma of the CRC group than in that of the healthy group. The results indicated that the presence of tumor cells does not reduce the degree of SHISA3 DNA in the peripheral blood of patients with CRC. In other words, the hypermethylation of SHISA3, which inactivates the gene, is a potential cause of tumorigenesis. Furthermore, the methylation rate of SHISA3 DNA was higher in the plasma of patients with stage II CRC than in that of those with stage I CRC. In conclusion, the combination of conventional testing and screening for SHISA3 hypermethylation in plasma could improve the rate at which CRC is detected.

A Novel Prognostic DNA Methylation Panel for Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related deaths. Discrepancies in clinical outcomes are observed even among patients with same-stage CRC due to molecular heterogeneity. Thus, biomarkers for predicting prognosis in CRC patients are urgently needed. We previously demonstrated that stage II CRC patients with NKX6.1 methylation had poor 5-year overall survival. However, the methylation frequency of NKX6.1 was only 23% in 151 pairs of CRC tissues. Thus, we aimed to develop a more robust prognostic panel for CRC using NKX6.1 in combination with three genes: LIM homeobox transcription factor 1α (LMX1A), sex-determining region Y-box 1 (SOX1), and zinc finger protein 177 (ZNF177). Through quantitative methylation analysis, we found that LMX1A, SOX1, and ZNF177 were hypermethylated in CRC tissues. LMX1A methylation was significantly associated with poor 5-year overall, and disease-free survivals in stage I and II CRC patients. Sensitivity and specificity analyses of the four-gene combination revealed the best sensitivity and optimal specificity. Moreover, patients with the four-gene methylation profile exhibited poorer disease-free survival than those without methylation. A significant effect of the four-gene methylation status on overall survival and disease-free survival was observed in early stage I and II CRC patients (p = 0.0016 and p = 0.0230, respectively). Taken together, these results demonstrate that the combination of the methylation statuses of NKX6.1, LMX1A, SOX1, and ZNF177 creates a novel prognostic panel that could be considered a molecular marker for outcomes in CRC patients.

NKX6.1 hypermethylation predicts the outcome of stage II colorectal cancer patients undergoing chemotherapy.

Colorectal cancer (CRC) is a common malignancy worldwide. CRC patients in the same stage often present with dramatically different clinical scenarios. Thus, robust prognostic biomarkers are urgently needed to guide therapies and improve treatment outcomes. The NKX6.1 gene has been identified as a hypermethylation marker in cervical cancer, functioning as a metastasis suppressor by regulating epithelial-mesenchymal transition. Here, we investigated whether hypermethylation of NKX6.1 might be a prognostic biomarker for CRC. By analyzing the methylation and expression of NKX6.1 in CRC tissues and CRC cell lines. We quantitatively examined the NKX6.1 methylation levels in 151 pairs of CRC tissues by using methylation-specific polymerase chain reaction analysis and found that NKX6.1 was hypermethylated in 35 of 151 CRC tissues (23%). NKX6.1 gene expression was inversely correlated with the DNA methylation level in CRC cell lines in vitro. Then, we analyzed the association of NKX6.1 methylation with clinical characteristics of these CRC patients. Our data demonstrated that patients with NKX6.1 methylation presented poorer 5-year overall survival (P = 0.0167) and disease-free survival (P = 0.0083) than patients without NKX6.1 methylation after receiving adjuvant chemotherapy. Most importantly, these data revealed that stage II CRC patients with NKX6.1 methylation had poorer 5-year disease-free survival (P = 0.0322) than patients without NKX6.1 methylation after adjuvant chemotherapy. Our results demonstrate that methylation of NKX6.1 is a novel prognostic biomarker in CRC and that it may be used as a predictor of the response to chemotherapy.

Risk of colorectal cancer in patients with periodontal disease severity: a nationwide, population-based cohort study.

BACKGROUND: Periodontal disease (PD) and colorectal cancer (CRC) were associated with chronic inflammation. This retrospective cohort study examined the association between PD severity and CRC in a large-scale, population-based Chinese cohort. METHODS: A total of approximately 106,487 individuals with newly diagnosed PD and 106,487 age-matched and sex-matched patients without PD from 2000 to 2002 were identified from Taiwan's National Health Insurance Research Database (NHIRD). RESULTS: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with PD than in those without PD (log-rank test, P < 0.001). After adjustment for age, sex, and comorbidities, patients with PD were associated with a significantly higher risk of CRC compared with those without PD (adjusted HR = 1.64, 95% CI = 1.50-1.80). Further, the risk of CRC appeared to increase with increasing frequency of PD medical visits [adjusted HR (95% CI) was 1.78 (1.58-2.02) and 1.53 (1.35-1.74) for annual visits > 10 and < 4, respectively]. CONCLUSION: Based on our study, PD severity was associated with an increase in the risk of CRC. Further mechanistic research is needed.

A Modified Bowel Preparation Regimen for Colonoscopy Providing the Patients' Satisfaction and Convenience.

BACKGROUND A complete cleansing of the bowel is a critical factor that impacts the diagnostic accuracy of colonoscopies. However, the common bowel preparation regimen of two 45 mL doses of sodium phosphate (2×NaP) often leads to uncomfortable symptoms and subsequently lower patient adherence. To improve patient adherence and satisfaction, we proposed a modified regimen composed of two sennoside tablets and one bottle of NaP (S+NaP) and we then evaluated bowel preparation quality and patient satisfaction. MATERIAL AND METHODS A total of 531 patients who underwent colonoscopies at the outpatient coloproctology clinic from January 2016 to December 2016 were retrospectively reviewed. Eligible patients were divided into two groups: S+NaP group (n=93) and 2×NaP group (n=60). We compared bowel preparation quality, adenoma detection rate (ADR), self-reported patient satisfaction scores, and adverse events among the two groups. RESULTS Regarding high bowel preparation quality, our results showed that there was no significant difference among the two groups (p=0.775), as well as no significant differences in ADRs (p=0.187). However, a lower proportion of nausea was found in the S+NaP group compared to the 2×NaP group (24.7% versus 41.7%, respectively, p=0.028). In addition, patients in the S+NaP group were more likely to be very satisfied with the regimen compared with patients in the 2×NaP group (odds ratio: 5.58; 95% confidence interval: 2.36-13.213, p<0.001). CONCLUSIONS Our modified bowel preparation regimen, S+NaP, yielded significantly higher patient satisfaction with less nausea while maintaining similar bowel preparation quality.

Rectal cancer with complete clinical response after neoadjuvant chemoradiotherapy, surgery, or "watch and wait".

PURPOSE: The purpose of this study was to compare the outcomes of patients treated with chemoradiotherapy with a complete clinical response followed by either a "watch and wait" strategy or a total mesorectal excision. METHODS: This was an observational retrospective study from a single institute. Patients with locally advanced rectal cancer following chemoradiotherapy with a complete clinical response from January 1, 2007 to December 31, 2014 were included. RESULTS: The study population consisted of 18 patients who opted for a "watch and wait" policy and 26 patients who underwent radical surgery after achieving a complete clinical response. Patients had no documented treatment complications under the watch and wait policy, while 13 patients who underwent radical surgery experienced significant morbidity. There were two local recurrences in the watch and wait group; both were treated with salvage resection and had no associated mortality. In the radical surgery group, 1 patient showed an incomplete pathologic response (ypT0N1), and the remaining 25 patients showed complete pathologic responses; 1 had a distant recurrence, which was managed non-operatively, and 2 patients died of unrelated causes. The 5-year overall survival rate and median disease-free survival time were 100% and 69.78 months in the watch and wait group and 92.30% and 89.04 months in the radical surgery group. CONCLUSIONS: A watch and wait policy avoids the morbidity associated with radical surgery and preserves oncologic outcomes in our retrospective study from a single institute. It could be considered a therapeutic option in patients with locally advanced rectal cancer following chemoradiotherapy with a complete clinical response.

Association between colonic diverticular disease and colorectal cancer: a nationwide population-based study.

BACKGROUND & AIMS: We investigated whether a diagnosis of colonic diverticular disease is associated with an increased risk for subsequent development of colorectal cancer (CRC) in a nationwide population-based retrospective study. METHODS: We identified 41,359 individuals diagnosed with colonic diverticular disease as inpatients from 2000 through 2009 from the Taiwan National Health Insurance Research Database (study cohort) and collected data for 165,436 randomly selected additional subjects, matched by sex, age, and baseline year (comparison cohort). Data were collected until individuals developed CRC or withdrew from the National Health Insurance system, or until December 31, 2010. Cumulative incidences and hazard ratios (HRs) of CRC development were determined. To assess for ascertainment bias, we conducted an analysis excluding the first 12 months of follow-up evaluation. RESULTS: The risk of CRC was significantly higher in the study cohort than in the comparison cohort (HR adjusted for age, sex, and comorbidities, 4.54; 95% confidence interval, 4.19-4.91; P < .0001). In a sensitivity analysis, we excluded the first 12 months of follow-up evaluation after a diagnosis of colonic diverticular disease; subsequent incidence rates for CRC in the study and comparison cohorts were 15.13 and 15.74 per 10,000 person-years, respectively (adjusted HR, 0.96; 95% confidence interval, 0.83-1.11). CONCLUSIONS: Colonic diverticular disease is not associated with an increased risk of subsequent CRC after the first year of diagnosis of colonic diverticular disease. An increased risk was observed in the first year, possibly owing to misclassification and screening effects.

Radiofrequency ablation of hepatic metastases: factors influencing local tumor progression.

BACKGROUND: Although radiofrequency ablation (RFA) of nonresectable hepatic metastases has gained wide acceptance by showing survival benefit in selected patients, scattered reports are available regarding risk factors of local control of percutaneous RFA. The purpose of this study was to prospectively evaluate the factors influencing local tumor progression after percutaneous RFA of hepatic metastases. METHODS: Sixty-nine hepatic metastatic lesions in 54 patients were treated by percutaneous RFA. Efficacy was evaluated by contrast-enhanced computed tomography or magnetic resonance imaging at 1 month after ablation, then at 3-month intervals for the first year and biannually thereafter. RESULTS: The results of the log-rank test showed that tumor size of <3 cm (p = 0.024) and the absence of tumor contiguous with large vessels (p = 0.002) significantly correlated with local control for hepatic metastases. Cox regression analysis showed that the tumor size <3 cm and the absence of tumor contiguous with large vessels were independent factors (p = 0.055 and 0.009, respectively). The results of the log-rank test showed that neither the threshold post-ablation margin of 1.8 cm (p = 0.064) nor the presence of a tumor with subcapsular location (p = 0.134) correlated with the success of local control. CONCLUSIONS: Percutaneous RFA is more effective in achieving local control in patients with hepatic metastases when the tumor size is <3 cm and not contiguous with large vessels.

Two-Person Colonoscopy as a Training Approach to Non-sedation Colonoscopy.

BACKGROUND: Reported learning curves of colonoscopy vary from 94 to 275 cases and focus on one-person colonoscopy. Our aim was to evaluate the learning curve of two-person non-sedation colonoscopy for trainees in a single tertiary care hospital. PATIENTS AND METHODS: We conducted a retrospective study in 1264 patients who underwent diagnostic or screening colonoscopies in a single institution from August 2012 to January 2013. Most of the patients (1174/1264) did not receive sedation during the procedure. All procedures were performed under two-person control. Two third-year residents who received previous colonoscopic training via a plastic model were the trainees. RESULTS: In comparison to the performance of 5 staff members, the colonoscopic outcomes showed no significant differences in the completion rates (77.2% vs. 79.8%, P = .382), average polyp numbers (.9 ± 1.7 vs. 1.0 ± 1.8, P = .453), polyp detection rates (43.5% vs. 46.3%, P = .434), or intubation lengths (96.4 ± 29.3 vs. 96.3 ± 26.7 cm, P = .939). The total procedure times for the 2 groups were 17.2 ± 10.6 minutes (trainees) and 12.9 ± 7.8 minutes (staff) (P < .001). CONCLUSION: Trainees achieved acceptable outcomes over an 81-97 case learning curve under a two-person non-sedation colonoscopy technique, an approach with potential as a transition to single-operator colonoscopy.

Anaesthesia mumps after laparoscopic right hemicolectomy under general anaesthesia: A case report.

INTRODUCTION: Anaesthesia mumps is an extremely rare postoperative complication that occurs following various surgical procedures after general anaesthesia. We aimed to contribute to the growing knowledge of potential clinical presentations, outcomes, and possible causes. PRESENTATION OF CASE: A 93-year-old man experienced acute swelling of a unilateral parotid gland 1 day after laparoscopic right hemicolectomy under general anaesthesia. The symptoms he presented with were acute, non-tender swelling in the left preauricular and submandibular triangle with well-marginated, circular swelling of the buccal mucosa. Amylase level was within the normal range. Computed tomography showed left preauricular soft tissue swelling and enlargement and an enhanced left parotid gland exhibiting inflammation. The swelling subsided after 3 days of conservative treatment. DISCUSSION: Anaesthesia mumps have been associated with a variety of surgeries, including colorectal surgery, and is a rare complication after the induction of general anaesthesia. Despite the few cases presenting with airway obstruction, the outcome for swelling of the parotid or submandibular gland is generally good. CONCLUSION: Early awareness of anaesthesia mumps and close evaluation lead to a fair prognosis for scar presentation.

Risk of Colorectal Cancer in Patients With Attention-Deficit Hyperactivity Disorder: A Nationwide, Population-Based Cohort Study.

Background: The association between attention-deficit hypersensitivity disorder (ADHD) and the risk of developing colorectal cancer (CRC) is, as yet, to be investigated, and thus, we have conducted this nationwide, cohort study to examine the association in patients from Taiwan. Methods: In this study, 798 individuals with newly diagnosed ADHD and 2,394 (1:3) age-, gender-, and index year- matched controls without ADHD were enrolled, between 2000 and 2013, from the Longitudinal Health Insurance Database, a subset of the National Health Insurance Research Database in Taiwan. The cumulative incidence of CRC was assessed in each cohort by the Kaplan-Meier method. The multivariate Cox proportional hazards model was used to estimate the crude, and the adjusted hazards ratios (HRs) with 95% confidence intervals (CIs), was conducted to estimate the association between ADHD and CRC. Results: The Kaplan-Meier analysis revealed that the cumulative incidence of CRC was significantly higher in patients with ADHD than in those without it (log rank test, p < 0.001). After adjustments for age, gender, comorbidities, and other covariates, the ADHD group was associated with an increased risk of CRC in comparison to the non-ADHD group (adjusted HR = 3.458, 95% CI = 1.640-7.293, p < 0.001). In addition, the usage of methylphenidate was not associated with the risk of developing CRC in patients with ADHD. Conclusion: This retrospective cohort study depicts the evidence that ADHD was associated with the increased risk of CRC. Further studies are needed to confirm the association and the underlying mechanisms.

Preservation of superior rectal artery in laparoscopically assisted subtotal colectomy with ileorectal anastomosis for slow transit constipation.

BACKGROUND: Slow transit constipation (STC) has traditionally been considered as a functional disorder. However, evidence is accumulating that suggests that most of the motility alterations in STC might be of a neuropathic etiology. If the patient does not meet the diagnosis of pelvic outlet obstruction and poorly response to conservative treatment, surgical intervention with subtotal colectomy may be effective. The most unwanted complication of the procedure is anastomotic leakage, however, preservation of the superior rectal artery (SRA) may reduce its incidence. AIM: To evaluate the preservation of the SRA in laparoscopically assisted subtotal colectomy with ileorectal anastomosis in STC patients. METHODS: This was a single-center retrospective observational study. STC was diagnosed after a series of examinations which included a colonic transit test, anal manometry, a balloon expulsion test, and a barium enema. Eligible patients underwent laparoscopically assisted total colectomy with ileorectal anastomosis and were examined between January 2016 and January 2018. The operation time, blood loss, time to first flatus, length of hospital days, and incidence of minor or major complications were recorded. RESULTS: A total of 32 patients (mean age, 42.6 years) who had received laparoscopic assisted subtotal colectomy with ileorectal artery anastomosis and preservation of the SRA. All patients were diagnosed with STC after a series of examinations. The mean operative time was 151 min and the mean blood loss was 119 mL. The mean day of first time to flatus was 3.0 d, and the mean hospital stay was 10.6 d. There were no any patients conversions to laparotomy. Post-operative minor complications including 1 wound infection and 1 case of ileus. There was no surgical mortality. No anastomosis leakage was noted in any of the patients. CONCLUSION: Laparoscopically assisted subtotal colectomy with ileorectal anastomosis and preservation of the SRA can significantly improve bowel function with careful patient selection. Sparing the SRA may protect against anastomosis leakage.

Iatrogenic colonic perforation by colonoscopy: a fatal complication for patients with a high anesthetic risk.

PURPOSE: Colonoscopy is currently a standard and widespread technique used in screening for colorectal cancer. Iatrogenic colonic perforation during colonoscopy is an unfortunate complication that can induce significant morbidity and even death. Here, we reviewed the clinical results of iatrogenic colonoscopic perforation in our hospital. METHODS: This was a retrospective review of 35,186 colonoscopies performed in the Tri-Service General Hospital, Taipei, Taiwan from January 1998 to December 2007. Patient demographic data, indications, comorbidities, operative history, perforation site, time of diagnosis, management, complications, hospital stay, and outcomes were recorded. RESULTS: In this 10-year period, 23 cases of iatrogenic colonic perforation were recorded (0.065%) affecting 11 men and 12 women. The mean age was 71.2 years. There were 13 patients in American Society of Anesthesiology (ASA) classifications 1 or 2 (low anesthetic risk, group A), and ten patients in ASA classes 3 or 4 (high anesthetic risk, group B). The mean hospital stay was 12 days in group A versus 23.5 days in group B (P = 0.002). Moreover, four patients in group B died (17%; P = 0.024). CONCLUSION: Colonoscopy-related perforation can progress to peritonitis and sepsis, resulting in serious morbidity or death. High-anesthetic risk patients with colonic perforation have a longer hospital stay and a poor prognosis. Hence, patients need to be informed of the complications of colonoscopy, and clinicians must be cautioned about the potential problems for patients with a high-anesthetic risk when performing the procedure.

Necrotizing fasciitis due to acute perforated appendicitis: case report.

Acute appendicitis is one of the most common surgical emergencies. Accurate diagnosis is often hindered due to various presentations that differ from the typical signs of appendicitis, especially the position of the appendix. A delay in treatment increases the likelihood of complications such as perforation, which is associated with an increase in morbidity and mortality rates. We herein present the case of a 76-year-old woman presenting with necrotizing fasciitis of the abdominal wall and right flank regions due to a perforated appendix. Such complication is extremely rare but life-threatening. It may be confused with cellulitis, causing a delay in aggressive treatment. This case represents an unusual complication of a common disease. Also, acute appendicitis or intra-abdominal pathologies should be taken into consideration in determining the cause of necrotizing fasciitis presenting over abdominal, flank, or perineal regions.

Risk of colorectal cancer in patients with alcoholism: A nationwide, population-based nested case-control study.

BACKGROUND: Colorectal cancer (CRC) is regarded as a multifactorial disease and shares many risk factors with alcoholism. However, the association between alcoholism and CRC remains controversial. OBJECTIVES: In this study, we aimed to evaluate the association between alcoholism and risk of CRC. METHODS: We performed a large-scale, population-based nested case-control study using the Longitudinal Health Insurance Database 2013, derived from Taiwan's National Health Insurance Research Database, and collected data from 2000 to 2013. There were 49,095 diagnosed cases of CRC defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Each case was matched with three controls by sex, age, index date of CRC, and annual medical visits; a total of 147,285 controls were identified. Multiple risk factors of CRC in alcoholism cases were investigated using unconditional multiple logistic regression analysis. RESULTS: Among 49,095 cases of CRC, alcoholism was associated with a significantly higher risk of CRC (adjusted odds ratio (OR), 1.631; 95% CI, 1.565-1.699) in multivariate logistic regression, after adjusting other CRC risk factors, and in stratified analysis with multivariate logistic regression. In addition, there was a time-dependent relationship between alcoholism duration and CRC risk in >1 year, > 2 years, >5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788-1.967, 1.948-2.158, 2.498-2.835, and 2.511-2.989 respectively). CONCLUSION: An association between alcoholism and risk of CRC was found in this study. Furthermore, patients with longer alcoholism history showed higher likelihood of developing CRC, which indicates a time-dependent relationship between alcoholism exposure and CRC. Further research on colorectal tumorigenesis is needed.

Author Correction: Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel methylation gene panel in adjacent normal tissues predicts poor prognosis of colorectal cancer in Taiwan.

BACKGROUND: It is evident that current clinical criteria are suboptimal to accurately estimate patient prognosis. Studies have identified epigenetic aberrant changes as novel prognostic factors for colorectal cancer (CRC). AIM: To estimate whether a methylation gene panel in different clinical stages can reflect a different prognosis. METHODS: We enrolled 120 CRC patients from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select six genes involved in carcinogenesis pathways. Patients were divided into two groups based on the methylation status of the six evaluated genes, namely, the < 3 aberrancy group and ≥ 3 aberrancy group. Various tumor stages were divided into two subgroups (local and advanced stages) on the basis of the pathological type of the following tissues: Tumor and adjacent normal tissues (matched normal). We assessed DNA methylation in tumors and adjacent normal tissues from CRC patients and analyzed the association between DNA methylation with different cancer stages and the prognostic outcome including time to progression (TTP) and overall survival. RESULTS: We observed a significantly increasing trend of hazard ratio as the number of hypermethylated genes increased both in normal tissue and tumor tissue. The 5-year TTP survival curves showed a significant difference between the ≥ 3 aberrancy group and the < 3 aberrancy group. Compared with the < 3 aberrancy group, a significantly shorter TTP was observed in the ≥ 3 aberrancy group. We further analyzed the interaction between CRC prognosis and different cancer stages (local and advanced) according to the methylation status of the selected genes in both types of tissues. There was a significantly shorter 5-year TTP for tumors at advanced stages with the promoter methylation status of selected genes than for those with local stages. We found an interaction between cancer stages and the promoter methylation status of selected genes in both types of tissues. CONCLUSION: Our data provide a significant association between the methylation markers in normal tissues with advanced stage and prognosis of CRC. We recommend using these novel markers to assist in clinical decision-making.

Multiple gene promoter methylation and clinical stage in adjacent normal tissues: Effect on prognosis of colorectal cancer in Taiwan.

This study provide an insight that the panel genes methylation status in different clinical stage tended to reflect a different prognosis even in matched normal tissues, to clinical recommendation. We enrolled 153 colorectal cancer patients from a medical center in Taiwan and used the candidate gene approach to select five genes involved in carcinogenesis pathways. We analyzed the relationship between DNA methylation with different cancer stages and the prognostic outcome. There were significant trends of increasing risk of 5-year time to progression and event-free survival of subjects with raising number of hypermethylation genes both in normal tissue and tumor tissue. The group with two or more genes with aberrant methylation in the advanced cancer stages (Me/advanced) had lower 5-year event-free survival among patients with colorectal cancer in either normal or tumor tissue. The adjusted hazard ratios in the group with two or more genes with aberrant methylation with advanced cancer stages (Me/advanced) were 8.04 (95% CI, 2.80-23.1; P for trend <0.01) and 8.01 (95% CI, 1.92-33.4; P for trend <0.01) in normal and tumor tissue, respectively. DNA methylation status was significantly associated with poor prognosis outcome. This finding in the matched normal tissues of colorectal cancer patients could be an alternative source of prognostic markers to assist clinical decision making.