Predictors for temporary stomas non-closure among non-metastatic rectal cancer patients undergoing curative resection: a retrospective analysis.

BACKGROUND: The primary treatment for non-metastatic rectal cancer is curative resection. However, sphincter-preserving surgery may lead to complications. This study aims to develop a predictive model for stoma non-closure in rectal cancer patients who underwent curative-intent low anterior resection. METHODS: Consecutive patients diagnosed with non-metastatic rectal cancer between January 2005 and December 2017, who underwent low anterior resection, were retrospectively included in the Chang Gung Memorial Foundation Institutional Review Board. A comprehensive evaluation and analysis of potential risk factors linked to stoma non-closure were performed. RESULTS: Out of 956 patients with temporary stomas, 10.3% (n = 103) experienced non-closure primarily due to cancer recurrence and anastomosis-related issues. Through multivariate analysis, several preoperative risk factors significantly associated with stoma non-closure were identified, including advanced age, anastomotic leakage, positive nodal status, high preoperative CEA levels, lower rectal cancer presence, margin involvement, and an eGFR below 30 mL/min/1.73m2. A risk assessment model achieved an AUC of 0.724, with a cutoff of 2.5, 84.5% sensitivity, and 51.4% specificity. Importantly, the non-closure rate could rise to 16.6% when more than two risk factors were present, starkly contrasting the 3.7% non-closure rate observed in cases with a risk score of 2 or below (p < 0.001). CONCLUSION: Prognostic risk factors associated with the non-closure of a temporary stoma include advanced age, symptomatic anastomotic leakage, nodal status, high CEA levels, margin involvement, and an eGFR below 30 mL/min/1.73m2. Hence, it is crucial for surgeons to evaluate these factors and provide patients with a comprehensive prognosis before undergoing surgical intervention.

Preoperative risk stratification of permanent stoma in patients with non-metastatic mid and low rectal cancer undergoing curative resection and a temporary stoma.

BACKGROUND: Although a temporary stoma can mitigate the severity of anastomotic leakage, some rectal cancer patients retain a permanent stoma after sphincter-preserving surgery. Therefore, this study aimed to identify independent preoperative risk factors for permanent stoma and establish a prediction model for mid-and low-rectal cancer patients who underwent sphincter-preserving surgery and temporary stoma. METHODS: We retrospectively reviewed consecutive patients with non-metastatic rectal cancer between 2000 and 2015. The risk factors for permanent stomas were collected and analyzed. RESULTS: A total of 1020 rectal cancer patients with temporary stoma were included. The overall rate of permanent stoma was 17.5% (n = 179). Cancer progression and anastomotic complications are major causes of permanent stomas. Multivariate analysis showed that preoperative risk factors such as advanced age, male sex, preoperative CEA ≥ 10 ng/ml, T4 stage, N stage, low rectal tumor, and ASA ≥ III were independent preoperative risk factors after adjustment. The ROC curve of the risk factors and permanent stoma showed an AUC of 0.689, a cut-off value of 2.5, a sensitivity of 0.689, and a specificity of 0.622. The permanent stoma rates were significantly higher between risk scores ≤ 2 and > 2 (29.9% vs. 11.3%, p < 0.001). CONCLUSION: Preoperative CEA ≥ 10 ng/ml, T4 stage, N stage, low rectal tumor, advanced age, ASA ≥ III, and male sex were independent preoperative prognostic factors for a permanent stoma. The risk was higher with a score greater than two. Therefore, the risk of subsequent permanent stoma should be evaluated and informed to the patient prior to the primary surgery.

Smoking cessation for less than 10 years remains a risk factor of anastomotic leakage in mid-to-low rectal cancer patients undergoing sphincter-preserving surgery.

PURPOSE: Although cigarette smoking is a well-known risk factor for anastomotic leakage during rectal surgery, the proper duration of smoking cessation that can decrease anastomotic leakage in patients undergoing sphincter-preserving surgery is unclear. This study aimed to investigate the optimal duration of smoking cessation that can reduce this complication. METHODS: Between January 1, 2000, and December 31, 2012, we enrolled 1246 consecutive patients who underwent curative-intent sphincter-preserving surgery without preventive stoma at the Division of Colorectal Surgery of a tertiary referral center in Taiwan. Questionnaires were used to record their pre-surgical smoking status. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off duration of smoking cessation. Multivariate analysis was used to verify the effect of cigarette cessation on anastomotic leakage. RESULTS: The ROC curve showed a cut-off value of 10.5 years of cessation duration. Therefore, the former-smoker group was further divided using a cessation duration of 10 years. The overall anastomotic leakage rate was 5.29%. However, the anastomotic leakage rate in current smokers (9.3%) and in those who quit for < 10 years (12.9%) was significantly higher than that in non-smokers (3.3%) and those who quit for ≥ 10 years (4.5%). On multivariate analysis, current smokers (p = 0.022), former smokers with < 10 years of smoking cessation (OR 2.725; p = 0.029), male sex (p = 0.015), and low rectal cancer (p < 0.001) were all independently related to the development of anastomotic leakage. CONCLUSION: Smoking cessation for < 10 years remains a risk factor for anastomotic leakage in patients with mid-to-low rectal cancer undergoing sphincter-preserving surgery.

A Prediction Model for Metachronous Peritoneal Carcinomatosis in Patients with Stage T4 Colon Cancer after Curative Resection.

(1) Background: The aim of this study was to develop a prediction model for assessing individual mPC risk in patients with pT4 colon cancer. Methods: A total of 2003 patients with pT4 colon cancer undergoing R0 resection were categorized into the training or testing set. Based on the training set, 2044 Cox prediction models were developed. Next, models with the maximal C-index and minimal prediction error were selected. The final model was then validated based on the testing set using a time-dependent area under the curve and Brier score, and a scoring system was developed. Patients were stratified into the high- or low-risk group by their risk score, with the cut-off points determined by a classification and regression tree (CART). (2) Results: The five candidate predictors were tumor location, preoperative carcinoembryonic antigen value, histologic type, T stage and nodal stage. Based on the CART, patients were categorized into the low-risk or high-risk groups. The model has high predictive accuracy (prediction error ≤5%) and good discrimination ability (area under the curve >0.7). (3) Conclusions: The prediction model quantifies individual risk and is feasible for selecting patients with pT4 colon cancer who are at high risk of developing mPC.

Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan.

Patients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%-89.9%) and 76.7% (95% CI = 37.2%-99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%-57.7%) and 49.3% (95% CI = 21.9%-84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

Survival analysis of local excision vs total mesorectal excision for middle and low rectal cancer in pT1/pT2 stage and intermediate pathological risk.

BACKGROUND: Local excision (LE) is a feasible treatment approach for rectal cancers in stage pT1 and presents low pathological risk, whereas total mesorectal excision (TME) is a reasonable treatment for more advanced cancers. On the basis of the pathology findings, surgeons may suggest TME for patients receiving LE. This study compared the survival outcomes between LE with/without chemoradiation and TME in mid and low rectal cancer patients in stage pT1/pT2, with highly selective intermediate pathological risk. METHODS: This retrospective study included 134 patients who received TME and 39 patients who underwent LE for the treatment of intermediate risk (pT1 with poor differentiation, lymphovascular invasion, perineural invasion, relatively large tumor, or small-sized pT2 tumor) rectal cancer between 1998 and 2016. RESULTS: Overall survival (OS), disease-free survival (DFS), and cumulative recurrence rate (CRR) were similar between the LE (3-year DFS 92%) and TME (3-year DFS 91%) groups. Following subgrouping into an LE with adjuvant therapy group and a TME without adjuvant therapy group, the compared survival outcomes (OS, DFS, and CRR) were found not to be statistically different. The temporary and permanent ostomy rates were higher in the TME group than in the LE group (p < 0.001). Rates of early and late morbidity following surgery were higher in the TME group (p = 0.005), and LE had similar survival compared with TME. CONCLUSION: For patients who had mid and low rectal cancer in stage pT1/pT2 and intermediate pathological risk, LE with chemoradiation presents an alternative treatment option for selected patients.

The impact of kidney function on colorectal cancer patients with localized and regional diseases: An observational study from Taiwan.

BACKGROUND: Impaired kidney function is associated with different diseases. However, its impact on colorectal cancer has not been clarified. In order to understand the effect of preoperative kidney function on the outcome of patients with cancer, we analyzed colorectal cancer patients with localized or regional diseases. MATERIALS AND METHODS: In total, 3731 stage I to III colorectal cancer (CRC) patients were analyzed in Chang Gung Memorial Hospital. Modification of Diet in Renal Disease (MDRD) formula was used for estimated glomerular filtration rate (eGFR). Receiver operating characteristic (ROC) analysis for kidney function cut-off value; Chi-square method, independent t test, or analysis of variance (ANOVA) method for clinicopathological factors; Kaplan-Meier method for disease-free survival (DFS); Cox proportional hazard model for multivariate analysis. RESULTS: Among colon cancer patients, low eGFR (MDRD <70) was associated with more male patients, T2 stage, patients without adjuvant chemotherapy, and patients with elevated creatinine level. Low eGFR is a significant risk factor only for stage III colon cancer (hazard ratio 1.70, 95% CI: 1.28-2.26; P < 0.001). Furthermore, postoperative adjuvant chemotherapy did not significantly increase 5-year DFS for both high and low eGFR groups in stage II patients (5 yrs DFS, 94.8% vs. 84.1%, P = 0.098 for high eGFR subgroup; and 75.0% vs. 75.8%, P = 0.379 for low eGFR subgroup). However, significant improvement of 5-yrs DFS after chemotherapy was found in low eGFR stage III colon cancer patients (64.7% vs. 39.4%, P < 0.001 for low eGFR subgroup). In contrast, no significant DFS difference was caused by chemotherapy for high eGFR stage III subgroup (70.5% vs. 63.9%, P = 0.110). CONCLUSIONS: Although low eGFR is an independent risk factor for stage III colon cancer. However, the adjuvant chemotherapy impacts on stage III colon cancer patients differently according to eGFR status.

Preoperative Carcinoembryonic Antigen as a Poor Prognostic Factor in Stage I-III Colorectal Cancer After Curative-Intent Resection: A Propensity Score Matching Analysis.

BACKGROUND: Preoperative carcinoembryonic antigen (CEA) has yet to be used as a prognostic or adjuvant chemotherapy factor for colorectal cancer (CRC). METHODS: This retrospective cohort study included all stage I-III CRC patients with different preoperative serum CEA levels (≤ 5, 5-10, and > 10 ng/ml) at a single center between 1995 and 2010. Propensity score matching was performed in a 1:1 ratio between the two elevated CEA groups (5-10 ng/ml and > 10 ng/ml) and in a 1:2 ratio between the elevated and non-elevated groups (≤ 5 ng/ml), with a caliper of 0.05. RESULTS: After exclusion and matching, 3857 patients had preoperative CEA levels ≤ 5 ng/ml, 1121 patients had CEA levels between 5 and 10 ng/ml, and 1121 patients had CEA levels > 10 ng/ml. Elevated preoperative CEA showed an increased risk of overall survival (5-10 ng/ml: hazard ratio [HR] 1.376; > 10 ng/ml: HR 1.523; both p < 0.001), cancer-specific survival (5-10 ng/ml: HR 1.404; > 10 ng/ml: HR 1.712; both p < 0.001), and recurrence free interval (5-10 ng/ml: HR 1.190; > 10 ng/ml: HR 1.468; both p < 0.05). Patients with negative lymph node staging (LNs) and CEA > 10 ng/ml, as well as those with positive LNs and CEA ≤ 5 ng/ml, showed similar overall survival (5-year survival: 72% vs. 69%; p = 0.542) and recurrence free intervals (19.9 vs. 21.72 months; p = 0.662). CONCLUSIONS: A preoperative CEA level can be an independent prognostic factor for stage I-III CRC after curative resection. Patients with negative LNs and preoperative CEA level > 10 ng/ml should be considered for intensive follow-up or adjuvant chemotherapy.

Primary tumor location in stage III colon cancer has prognostic impact on subsequent liver metastasis.

BACKGROUND AND OBJECTIVES: We aim to investigate whether a difference exists between right-sided and left-sided colon cancer at the same disease stage and subsequent liver metastasis and identify whether tumor location can independently influence survival. METHODS: Right-sided colon cancer was defined as malignancy arising from the cecum to the transverse colon; left-sided colon cancer was defined as malignancy arising from the splenic flexure to the sigmoid colon. Clinicopathological features and survival data were collected for analysis. RESULTS: Overall, 1442 patients were included for analysis. The median follow-up time was 58.2 months. Patients with left-sided colon cancer had better 5-year overall survival (75.2% vs 61.7%, P = 0.005), 5-year cancer-specific survival (81.6% vs 73.4%, P = 0.001), and 5-year recurrence-free survival (70.9% vs 66.5%, P = 0.033) compared with patients having right-sided colon cancer. After the presentation of subsequent liver metastasis, patients with primary left-sided colon cancer had better 3-year cancer-specific survival ( P < 0.001). In the multivariate analysis, cancer location was an independent prognostic factor for cancer-specific survival (right vs left, HR: 1.276, 95% CI: 1.002-1.625). CONCLUSIONS: The primary tumor location can serve as a prognostic factor for treatment outcomes either in primary stage III colon cancer or subsequent liver metastasis.

EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome.

BACKGROUND/AIM: Epidermal growth factor receptor (EGFR), mothers against decapentaplegic homolog 7 (SMAD7) and transforming growth factor betta (TGFB) are crucial for colorectal cancer (CRC) tumorigenesis. This study investigated whether polymorphisms in EGFR, SMAD7, and TGFB are associated with CRC risk in patients with Lynch syndrome. MATERIALS AND METHODS: Genotyping was performed using Sequenom iPLEX MassArray. Association between genetic polymorphisms and CRC was assessed using a weighted Cox proportional hazard model. RESULTS: Patients carrying the AA genotype of EGFR rs2227983 had a significantly higher CRC risk than those carrying the G allele (HR=2.55, 95% CI=1.25-5.17). The dominant model of SMAD7 rs12953717 (CT + TT genotypes) significantly increased CRC risk (HR=2.17, 95% CI=1.12-4.16) when compared to the wild-type CC genotype. Similarly, the GG genotype of TGFBR2 rs6785358 significantly increased the risk of CRC (HR=21.1, 95% CI=5.06-88.1) compared to the AA genotype. CONCLUSION: EGFR, SMAD7, and TGFBR2 are associated with CRC risk in patients with Lynch syndrome.

The dark side of laparoscopic surgery for colorectal cancer patients aged 75 years or older.

PURPOSE: The rate of postoperative morbidity and mortality is reportedly high in patients aged ≥ 75 years with colorectal cancer (CRC). In such patients, a comparison of the short-term outcome between open method and laparoscopy has not been clearly defined in Taiwan. We aimed to compare postoperative morbidity and mortality parameters after open method and laparoscopy in CRC patients aged ≥ 75 years. METHODS: We retrospectively analyzed patients who underwent surgery for CRC from February 2009 to September 2015 at the Linkou Chang Gung Memorial Hospital in Taiwan and analyzed their clinicopathological factors. Postoperative morbidity and mortality were analyzed for evaluating if laparoscopic surgery offers more favorable outcomes than open surgery in the elderly. RESULTS: A total of 1133 patients were enrolled and analyzed in this study; they were divided into two groups (open method vs. laparoscopy = 797 vs. 336). The anastomotic leakage rate was significantly higher in the laparoscopy group than in the open method group (3.3 vs. 0.9%, p = 0.003). Overall postoperative morbidity and mortality rates showed no significant difference between these two groups. Postoperative hospital stay was significantly shorter in the laparoscopy group than in the open method group (10.4 ± 8.7 vs. 13.8 ± 13.5 days, p < 0.001). CONCLUSIONS: Our results suggest that laparoscopy in patients aged ≥ 75 years with CRC had higher anastomosis leakage rate compared with open surgery but is acceptable and offers the benefit of a shorter hospital stay over open surgery.

Various clinicopathological features of patients with metachronous colorectal cancer in relation to different diagnostic intervals.

BACKGROUNDS: Clinicopathologic factors relating to developing metachronous colorectal cancer (CRC) have been reported. However, the effects of different diagnostic intervals on these risk factors required further analysis. PATIENTS AND METHODS: This retrospective study comprised 14,481 patients diagnosed from January 1995 to December 2012. Metachronous CRC was defined as the occurrence of a second colorectal cancer at least 1 year post-operatively. RESULTS: A total of 153 (1.06%) patients developed metachronous CRCs during the follow-up. Significantly higher rates of developing metachronous cancer occurred in male patients (1.2 vs 0.9%), patients with synchronous CRC (2.0 vs 1.0%), and patients with a positive family history of CRC (1.4 vs 0.9%). Pertaining to diagnostic intervals related to clinicopathological features, more severe staging was significant in the diagnostic interval between 2 and 3 years (35 vs 7.7%, 20.6%, 17.5%, P = .01) compared with other intervals. Male patients were more frequently detected to have CRC within 3 years compared with females (53.1 vs 29.1%, P = .005). For a diagnostic interval ≧ 5 years, a significantly higher rate of metachronous CRC located at the right colon was observed than that located at the left colon (36.6 vs 19.7%, p = 0.03). CONCLUSIONS: We evinced that a diagnostic interval between 2 and 3 years was a key time for metachronous CRC diagnosis with worse staging distribution. Based on current findings, we recommend the stratification of metachronous CRCs into diagnostic intervals of 1-2, 2-3, and ≧ 3 years, as they exhibit significantly different characteristics.

Polymorphisms of DNA repair genes are associated with colorectal cancer in patients with Lynch syndrome.

BACKGROUND: DNA repair genes are crucial for maintaining genomic stability by preventing mutagenesis and carcinogenesis. The present retrospective cohort study aimed at investigating whether MLH1, APEX1, MUTYH, OGG1, NUDT1, XRCC5, XPA, and ERCC2 single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in Chinese population with Lynch syndrome. METHODS: From Amsterdam criteria family registry, we identified 270 patients with Lynch syndrome. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between DNA repair SNPs and CRC were calculated using a weighted Cox proportional hazard regression model. RESULTS: Heterozygous variants of rs1799832 in NUDT1 (HR = 2.97, 95% CI = 1.51-5.83) and rs13181 in ERCC2 (HR = 2.69, 95% CI = 1.10-6.55) were significantly associated with an increased risk of CRC compared with wild-type homozygous CC and TT genotypes, respectively. However, the variant CG+GG genotype of MUTYH rs3219489 was associated with a decreased risk of CRC (HR = 0.49, 95% CI = 0.26-0.91) compared with the homozygous CC wild-type counterparts. CONCLUSION: Our findings revealed that polymorphisms of DNA repair genes that include NUDT1, ERCC2, and MUTYH are associated with CRC in patients with Lynch syndrome in Chinese population. Further studies with large sample size are needed to confirm our findings.

Polymorphisms of xenobiotic-metabolizing genes and colorectal cancer risk in patients with lynch syndrome: A retrospective cohort study in Taiwan.

Cytochrome P450 (CYP), glutathione-S-transferase (GST), and N-acetyltransferase (NAT) are crucial for metabolism and clearance of xenobiotics. This study investigated whether CYP, GST, and NAT single nucleotide polymorphisms (SNPs) are associated with colorectal cancer (CRC) in patients with Lynch syndrome. The interaction between these SNPs and cigarette smoking or meat consumption was also explored. We identified 270 patients with Lynch syndrome from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence interval (CIs). The GSTA1 rs3957356 TT (HR = 5.36, 95% CI = 2.39-12.0) and CYP1B1 rs1056836 CC (HR = 7.24, 95% CI = 3.51-14.9) were significantly associated with CRC risk when compared to wild-type CC and GG genotypes, respectively. However, the CYP1A1 rs4646903 CC genotype significantly reduced the risk of CRC (HR = 0.33, 95% CI = 0.12-0.89) when compared to TT genotype. Moreover, significant interactions were observed between NAT1 acetylation and CYP1B1 rs1056827 and meat consumption.Our results suggest that xenobiotic-metabolizing SNPs are not only associated with CRC risk in patients with Lynch syndrome in Taiwan but also interact with meat consumption to modify the disease risk. Environ. Mol. Mutagen. 59:69-78, 2018. © 2017 Wiley Periodicals, Inc.

Preoperative alkaline phosphatase elevation was associated with poor survival in colorectal cancer patients.

PURPOSE: Purpose To assess preoperative serum alkaline phosphatase (ALP) levels in colon adenocarcinomapatients with various clinical features and determine its prognostic value. METHODS: Between 2000 and 2013, 10,800 stage I-IV colon cancer patients who underwent surgery wereretrospectively enrolled. The relationship between ALP level and variables, including age, gender,carcinoembryonic Antigen (CEA) levels, aspartate aminotransferase (AST) level, bilirubin level, tumor size,liver cirrhosis, hepatitis, albumin level, histological type, and TNM-stage, were evaluated. The impact of ALP level elevation on survival was evaluated. RESULTS: Significant elevations in ALP level were found in patients with CEA ≥5 ng/ml (p<0.001); AST |≥43 U/L (p<0.001); total bilirubin ≥1.5 U/L (p<0.001); liver cirrhosis (p<0.001); albumin; <3.5g/dL (p <0.001); and stage IV disease (p=0.03).Patients with elevated ALP levels had significantly worse 5-year overall survival (OS) for colon (5-year OSrate: 71.5% vs. 78.3%, p<0.001; Fig. 1a) and rectal (5-year OS rate: 64.5% vs. 72.3%, p<0.001; Fig. 1b)cancer than patients with normal ALP levels. CONCLUSIONS: Elevated preoperative ALP levels was not only associated with liver disease, but it was alsorelated with advanced tumor status, and indicated a poor survival in colon and rectal cancer patients.

Polymorphisms of MTHFR C677T and A1298C associated with survival in patients with colorectal cancer treated with 5-fluorouracil-based chemotherapy.

BACKGROUND: This study examined the association between methylenetetrahydrofolate reductase (MTHFR) polymorphisms and survival of patients with colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)-based chemotherapy in Taiwan. METHODS: We genotyped MTHFR polymorphisms C677T (rs1801133) and A1298C (rs1801131) for 498 CRC patients treated with 5-FU-based chemotherapy after receiving surgery. Survival analyses on MTHFR polymorphisms were performed using log-rank test and Kaplan-Meier curve. Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MTHFR genotypes and survival. RESULTS: Overall survival (OS) was significantly longer in CRC patients with MTHFR 677 CT+TT genotypes compared with those with 677 CC genotype (HR 0.77; 95% CI 0.60-0.98). Although the MTHFR A1298C polymorphism was not associated with OS in CRC, this polymorphism was associated with significantly shorter OS in rectal cancer. Among rectal cancer patients, OS was shorter for patients with AC+CC genotypes than for those with the AA genotype (HR 1.95; 95% CI 1.35-2.83). In haplotype analysis, better OS was found for colon cancer patients carrying the MTHFR 677T-1298A haplotype (HR 0.73; 95% CI 0.55-0.97), but worse survival was linked to rectal cancer patients carrying the MTHFR 677C-1298C haplotype (HR 1.53; 95% CI 1.08-2.18). CONCLUSIONS: Our findings suggest that MTHFR genotypes provide prognostic information for CRC patients treated with 5-FU-based chemotherapy.

DNA Methylation Identifies Loci Distinguishing Hereditary Nonpolyposis Colorectal Cancer Without Germ-Line MLH1/MSH2 Mutation from Sporadic Colorectal Cancer.

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 presentation, histopathological features, and carcinogenesis of FCCTX resemble those of sporadic MMR-proficient colorectal tumors. It is of interest to obtain biomarkers that distinguish FCCTX from sporadic microsatellite stable (MSS) CRC, to develop preventive strategies. METHODS: The tumors and adjacent normal tissues of 40 patients with HNPCC were assayed using the Illumina Infinium HumanMethylation27 (HM27) BeadChip to assess the DNA methylation level at about 27,000 loci. The germ-line mutation status of MLH1 and MSH2 and the microsatellite instability status in these patients were obtained. Genome-wide DNA methylation measurements of three groups of patients with general CRC were downloaded from public domain databases. Probes with DNA methylation levels that differed significantly between patients with sporadic MSS CRC and FCCTX were examined, to explore their potential as biomarkers. RESULTS: We found that MSS HNPCC tumors were overwhelmingly hypomethylated compared with those from patient groups with other types of CRC, including germ-line MLH1/MSH2-mutated HNPCC and sporadic MSS CRC. Five gene-marker panels that exhibited a sensitivity of 100% and a specificity higher than 90% in both discovery and validation cohorts were proposed to distinguish MSS HNPCC tumors from sporadic MSS CRC. CONCLUSIONS: Our results warrant further investigation and validation. The loci identified here may become useful biomarkers for distinguishing between FCCTX and sporadic MSS CRC tumors.

TP53 Polymorphisms and Colorectal Cancer Risk in Patients with Lynch Syndrome in Taiwan: A Retrospective Cohort Study.

BACKGROUND AND AIM: TP53 encodes p53, which has a crucial role in modulating genes that regulate defense against cancer development. This study investigated whether TP53 polymorphisms are associated with colorectal cancer (CRC) in patients with Lynch syndrome and whether TP53 interacts with lifestyle factors to modify CRC risk. METHODS: We identified 260 MLH1 and MSH2 germline mutation carriers from the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A weighted Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association of TP53 polymorphisms with CRC development. RESULTS: The carriers of the variant C allele of rs1042522 were associated with a decreased CRC risk (GC genotype: HR = 0.35, 95% CI = 0.14-0.86; CC genotype: HR = 0.28, 95% CI = 0.13-0.57). In addition, the dominant model of rs1042522 was associated with a decreased CRC risk (HR = 0.32, 95% CI = 0.15-0.67). The CRC risk was decreased in carriers with the CT and TT genotypes of rs12947788 (HR = 0.20, 95% CI = 0.08-0.46 and HR = 0.25, 95% CI = 0.09-0.65, respectively). Moreover, the dominant model of rs12947788 was significantly associated with a decreased CRC risk (HR = 0.21, 95% CI = 0.09-0.46). A haplotype analysis indicated that compared with the most common GC haplotype, the CT haplotype was associated with a decreased CRC risk (HR = 0.26, 95% CI = 0.11-0.59). However, no significant interaction was observed between TP53 polymorphisms and lifestyle factors. CONCLUSION: The study results revealed that the rs1042522 genotype with the C allele and the rs12947788 genotype with the T allele in TP53 were associated with a decreased CRC risk in patients with Lynch syndrome in Taiwan.

Circulating Tumor Cell Count Correlates with Colorectal Neoplasm Progression and Is a Prognostic Marker for Distant Metastasis in Non-Metastatic Patients.

Enumeration of circulating tumor cells (CTCs) has been proven as a prognostic marker for metastatic colorectal cancer (m-CRC) patients. However, the currently available techniques for capturing and enumerating CTCs lack of required sensitivity to be applicable as a prognostic marker for non-metastatic patients as CTCs are even more rare. We have developed a microfluidic device utilizing antibody-conjugated non-fouling coating to eliminate nonspecific binding and to promote the multivalent binding of target cells. We then established the correlation of CTC counts and neoplasm progression through applying this platform to capture and enumerate CTCs in 2 mL of peripheral blood from healthy (n = 27), benign (n = 21), non-metastatic (n = 95), and m-CRC (n = 15) patients. The results showed that the CTC counts progressed from 0, 1, 5, to 36. Importantly, after 2-year follow-up on the non-metastatic CRC patients, we found that those who had ≥5 CTCs were 8 times more likely to develop distant metastasis within one year after curable surgery than those who had <5. In conclusion, by employing a sensitive device, CTC counts show good correlation with colorectal neoplasm, thus CTC may be as a simple, independent prognostic marker for the non-metastatic CRC patients who are at high risk of early recurrence.

Association between polymorphisms of APE1 and OGG1 and risk of colorectal cancer in Taiwan.

AIM: To evaluate the effects of OGG1 (Ser326Cys, 11657A/G, and Arg154His) and APE1 (Asp148Glu, and T-656G) polymorphisms on colorectal cancer (CRC) risk. METHODS: We enrolled 727 cases newly diagnosed with colorectal adenocarcinoma and 736 age- and sex-matched healthy controls from a medical center in Taiwan. Genomic DNA isolated from the buffy coat was used for genotyping through polymerase chain reaction. Unconditional logistic regressions were used for calculating ORs and 95%CIs to determine the association between the genetic polymorphisms and CRC risk. Haplotype frequencies were estimated using PHASE software. Moreover, stratification analyses on the basis of sex, age at diagnosis, and tumor subsite and stage were performed. RESULTS: The CRC risk was higher in patients with the OGG1 326Ser/Cys + Cys/Cys genotype (OR = 1.38, 95%CI: 1.03-1.85, P = 0.030), particularly high in patients with stage III + IV cancer (OR = 1.48, 95%CI: 1.03-2.13) compared with patients with the Ser/Ser genotype. In addition, OGG1 11657G allele carriers had a 41% reduced CRC risk among stage 0-II patients (OR = 0.59, 95%CI: 0.35-0.98). The CRC risk was significantly higher among females with the APE1 Glu allele (OR = 1.41, 95%CI: 1.02-1.96). The APE1 148Glu/-656G haplotype was also associated with a significant CRC risk in females (OR = 1.36, 95%CI: 1.03-1.78). CONCLUSION: OGG1 and APE1 polymorphisms are associated with stage- and sex-specific risk of CRC in the Taiwanese population.