Features Of Colorectal Cancer Research Articles

Clinical features of colorectal cancer patients in advanced age: a population-based approach.

In the immediate future, the number of geriatric patients will continue to rise; consequently we should expect an increase of colorectal cancer, a disease of the elderly population. Through the data of a Cancer Registry, we examined (a) the effect of ageing on the main features of colorectal cancer; (b) changes in management, especially for individuals older than 80years; and (c) changes in prognosis and survival in subgroups of patients with different age. The Registry provided information on colorectal cancer up to 2010 (27years). A total of 5293 patients were registered; these were divided into three groups: A (0-64years), B (65-79) and C (80 or more). Three periods of observation were chosen: 1 (1984-1992), 2 (1993-2001) and 3 (2001-2010). Group A included 1571 patients (29%), Group B 2539 (48%) and Group C 1183 (22.3%). The fraction of old individuals increased during the 27years of the investigation. In these patients, tumours were predominantly localized to the right colon (42.6%). The rate of surgery and ratio between curative and palliative approaches were similar among the three groups (p<0.38). There was disparity (p<0.002) in the administration of chemotherapy (5.8% of the elderly vs 34.4% in remaining patients). Survival increased over time in all three groups. In the elderly, average 5-year survival was 31% in period 1 and 55% in period 3. These data show that in Western countries, the standard of care for colorectal cancer diagnosed in geriatric patients has improved over the last 30years.

Clinic and pathologic features of colorectal cancer in patients less than or equal to 30 years of age.

e14591 Background: Early-onset colorectal cancer is rare. The aim of this study is to characterize those patients. Methods: Medical records of 5212 colorectal cancer patients were reviewed referred...

Comprehensive molecular characterization of colorectal cancer reveals genomic predictors of immune cell infiltrates.

3505 Background: Colorectal cancer (CRC) is a molecularly heterogeneous disease that arises and progresses in the context of a complex microenvironment. Tumor immune cell infiltrates have been show...

Proteomic features of colorectal cancer independently predict relapse-free survival.

616 Background: Proteomic analysis continues to provide major insight into the pathophysiology of colorectal cancer (CRC). Recently, the Cancer Genome Atlas Project and others have utilized reverse-phase protein arrays (RPPAs) to identify critical protein markers and signaling pathways in a variety of tumor types. However, the prognostic relevance of many of these proteins remains unclear. We utilized RPPA to analyze stage 2 and 3 CRC to investigate the prognostic implications of the functional proteome. Methods: Protein extraction was performed on 232 snap frozen stage 2/3 samples from the MD Anderson Cancer Center with a median 5 year follow up. 163 validated proteins and phospho-proteins were analyzed by RPPA (with dichotomization by the median value), and used to identify protein predictors of tumor recurrence. Cox regression was used for univariate analysis with bootstrap validation, followed by inclusion of proteins with corrected p≤ 0.05 into multivariate model with clinical and pathologic variables, including stage, grade, and microsatellite status. Results: 12 proteins were found to be significant predictors of tumor recurrence on univariate analysis after bootstrap validation, which are notable for components of the energy balance/MTOR signaling pathway including AMPK, mTOR, PI3 Kinase p85, FoxO3a. On multivariate analysis, inclusive of known prognostic clinical and pathology variables, phospho-Bad (Ser112), FoxO3a, HER3, and phospho-S6 (Ser240-244) remained significant. Conclusions: Functional proteomic analysis has identified key proteomic features with prognostic importance independent of known clinical/pathological variables. Confirmation studies are ongoing to explore regulators of energy balance and apoptosis in colorectal cancer. [Table: see text]

Clinical and epidemiological features of colorectal cancer in Dalian

Clinical and epidemiological features of colorectal cancer in Dalian

The proto-oncogene PBF binds p53 and is associated with prognostic features in colorectal cancer.

The PTTG1-binding factor (PBF) is a transforming gene capable of eliciting tumor formation in xenograft models. However, the precise role of PBF in tumorigenesis and its prognostic value as a cancer biomarker remain largely uncharacterised, particularly in malignancies outside the thyroid. Here, we provide the first evidence that PBF represents a promising prognostic marker in colorectal cancer. Examination of a total of 39 patients demonstrated higher PBF expression at both the mRNA (P = 0.009) and protein (P < 0.0001) level in colorectal tumors compared to matched normal tissue. Critically, PBF was most abundant in colorectal tumors associated with Extramural Vascular Invasion (EMVI), increased genetic instability (GI) and somatic TP53 mutations, all features linked with recurrence and poorer patient survival. We further demonstrate by glutathione-S-transferase (GST) pull-down and coimmunoprecipitation that PBF binds to the tumor suppressor protein p53, as well as to p53 mutants (Δ126-132, M133K, V197E, G245D, I255F and R273C) identified in the colorectal tumors. Importantly, overexpression of PBF in colorectal HCT116 cells interfered with the transcriptional activity of p53-responsive genes such as mdm2, p21 and sfn. Diminished p53 stability (> 90%; P < 0.01) was also evident with a concurrent increase in ubiquitinated p53. Human colorectal tumors with wild-type TP53 and high PBF expression also had low p53 protein levels (P < 0.05), further emphasizing a putative interaction between these genes in vivo. Overall, these results demonstrate an emerging role for PBF in colorectal tumorigenesis through regulating p53 activity, with implications for PBF as a prognostic indicator for invasive tumors.

Identification and characterization of colorectal cancer using Raman spectroscopy and feature selection techniques.

This study aims to detect colorectal cancer with near-infrared Raman spectroscopy and feature selection techniques. A total of 306 Raman spectra of colorectal cancer tissues and normal tissues are acquired from 44 colorectal cancer patients. Five diagnostically important Raman bands in the regions of 815-830, 935-945, 1131-1141, 1447-1457 and 1665-1675 cm(-1) related to proteins, nucleic acids and lipids of tissues are identified with the ant colony optimization (ACO) and support vector machine (SVM). The diagnostic models built with the identified Raman bands provide a diagnostic accuracy of 93.2% for identifying colorectal cancer from normal Raman spectroscopy. The study demonstrates that the Raman spectroscopy associated with ACO-SVM diagnostic algorithms has great potential to characterize and diagnose colorectal cancer.

Relationships between p16 gene promoter methylation and clinicopathologic features of colorectal cancer: a meta-analysis of 27 cohort studies.

Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.

The Clinical Utility of the Combination of T Stage and Venous Invasion to Predict Survival in Patients Undergoing Surgery for Colorectal Cancer

To examine the clinical utility of improved detection of venous invasion (VI) in patients undergoing potentially curative resection of colorectal cancer. VI is a feature of colorectal cancer (CRC) progression. Elastica staining can be used to improve detection of VI and correspondingly its prediction of patient survival. A single-center, observational study of pathology variables, including detection of VI by staining for elastica, using 631 stage I to III CRC specimens, collected from 1997 to 2009 (176 analyzed retrospectively and 455 analyzed prospectively), was performed. VI was detected in 56% of patients with CRC. Over a median follow-up period of 73 months, 238 patients died (134 from cancer). On multivariate analysis, VI by elastica staining was associated with a shorter survival duration, independent of other pathology features, in all cases [hazard ratio (HR) = 3.94, 95% confidence interval (CI): 2.33-6.65, P < 0.001] and in node-negative cases (HR = 3.55, 95% CI: 1.81-6.97; P < 0.001). In the absence of elastica-detected VI, with the exception of T stage, no other pathology features were associated with survival time. Therefore, the combination of T stage and VI (TVI) on survival was examined. Five-year cancer mortality could be stratified between 100% and 54% for patients with node-negative tumors and between 100% and 33% for patients with node-positive tumors. In all cases, the TVI had similar predictive value as that of T stage and node status (TNM). In node-negative disease, TVI had superior predictive value. The results of the present study have prompted the development of a novel tumor staging system based on TVI. The TVI has clinical utility, especially in node-negative disease, in predicting outcome following curative resection for CRC.

Limited diagnostic value of microsatellite instability associated pathology features in colorectal cancer

To determine the diagnostic test characteristics and inter-observer variation of pathology features for identifying high microsatellite instability (MSI-H) colorectal cancer (CRC). Six pathologists blindly evaluated 177 CRC for the presence of MSI-H associated pathology features. Inter-observer agreement was determined by using Kappa-statistics. In the first random 88/177 cases, mucinous carcinoma, tumor-infiltrating lymphocytes (TIL) and Crohns-like infiltrate (CLI) were the best discriminators between MSI-H and microsatellite stable CRC [OR 5.6 (95% CI 1.7-19), 5.4 (1.8-17) and 3.5 (1.1-11), respectively], with high specificity (89-91%). The sensitivities for MSI-H, however, were low (31-41%). In addition, inter-observer agreement was moderate for TIL and CLI (κ 0.38 and 0.48, respectively), but very good for mucinous carcinoma (κ 0.86). Interpretation of overall histopathology as suggestive for MSI-H performed better than any individual feature; OR 15 (5.2-44), and area under the curve 0.79. However, inter-observer agreement was moderate (κ 0.53). In the second set, TIL and CLI were scored according to updated scoring systems. Although both remained the best individual discriminators, test characteristics and inter-observer agreement did not improve. MSI-H pathology features have moderate accuracy for identifying MSI-H CRC, and are identified with moderate inter-observer agreement. These findings highlight the limitations of clinical strategies, such as the revised Bethesda guidelines, which incorporate the MSI-H associated pathology features in their strategy to identify persons with lynch syndrome.

Fusobacterium in Colonic Flora and Molecular Features of Colorectal Carcinoma

Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified overrepresentation of Fusobacterium in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fusobacterium status and molecular features in colorectal cancers through quantitative real-time PCR in 149 colorectal cancer tissues, 89 adjacent normal appearing mucosae and 72 colonic mucosae from cancer-free individuals. Results were correlated with CpG island methylator phenotype (CIMP) status, microsatellite instability (MSI), and mutations in BRAF, KRAS, TP53, CHD7, and CHD8. Whole-exome capture sequencing data were also available in 11 cases. Fusobacterium was detectable in 111 of 149 (74%) colorectal cancer tissues and heavily enriched in 9% (14/149) of the cases. As expected, Fusobacterium was also detected in normal appearing mucosae from both cancer and cancer-free individuals, but the amount of bacteria was much lower compared with colorectal cancer tissues (a mean of 250-fold lower for Pan-fusobacterium). We found the Fusobacterium-high colorectal cancer group (FB-high) to be associated with CIMP positivity (P = 0.001), TP53 wild-type (P = 0.015), hMLH1 methylation positivity (P = 0.0028), MSI (P = 0.018), and CHD7/8 mutation positivity (P = 0.002). Among the 11 cases where whole-exome sequencing data were available, two that were FB-high cases also had the highest number of somatic mutations (a mean of 736 per case in FB-high vs. 225 per case in all others). Taken together, our findings show that Fusobacterium enrichment is associated with specific molecular subsets of colorectal cancers, offering support for a pathogenic role in colorectal cancer for this gut microbiome component.

BRAF refines clinical interpretation of mismatch repair deficiency in colorectal cancer

1 ISSN 1758-194X 10.2217/CRC.13.83 © 2014 Future Medicine Ltd Colorect. Cancer (2014) 3(1), 1–4 *Department of Oncology, Vejle Hospital, DK-7100 Vejle, Denmark; Tel.: +45 79406802/+45 79406000; Fax: +45 79406907; lars.henrik.jensen@rsyd.dk Reliable TNM classification is mandatory in order to advise colorectal cancer patients regarding prognosis and optimal choice of treatment strategy. Despite the revolution in molecular biology, molecular markers have had a minor role in the initial characterization of colorectal cancer. It is now time to not only use immunohistochemical ana lysis of the mismatch repair (MMR) system, but also BRAF as the standard screening strategy in every new colorectal cancer. It is well known that the MMR system is clinically relevant for prognosis, heredity and treatment choices, but it is now becoming clearer that knowledge of BRAF status further supports all of these important questions. Other prerequisites for carrying out BRAF testing in the daily clinic – availability, fair price and reliability – have also been sufficiently satisfied.

Determinants of anemia in screen-detected colorectal cancer.

430 Background: Anaemia is an important clinical feature in colorectal cancer, since it may result in blood transfusion that may in turn compromise long term survival. The aim of the present study was to examine the relationship between tumour and host features, and anaemia in patients undergoing surgery for screen detected colorectal cancer. Methods: A prospectively maintained database of patients with cancer detected through a population based faecal occult blood test (FOBt) screening programme was analysed. Preoperative anaemia was defined as Hb&lt;115 g/l in females and Hb&lt;130 g/l in males. The amount of blood in the stool was classified on the degree of positivity of the FOBt (strong/weak) and the SIR was measured by the preoperative neutrophil to lymphocyte ratio (NLR&gt;5/NLR&lt;5). Results: A total of 263 patients were included: 174 (66%) males, 49 (19%) rectal, 177 (67%) node negative. Preoperative anaemia was present in 61 (23%) patients. The presence of anaemia was associated with more advanced T-stage (5% T1 vs. 42% T4, p&lt;0.001), advanced N-stage (18% N0 vs. 45% N2, p=0.001), and the presence of a right-sided tumour (44% vs. 14%, p&lt;0.001). In addition, anaemia was more likely to be present in patients with a strongly positive FOBt (30% strong vs. 19% weak, p=0.034), and in patients with an elevated SIR (44% vs 22%, p=0.045). Right-sided tumours were more likely to be strongly positive on FOBt compared to left-sided tumours (43% vs. 34%, p=0.053). Furthermore, strong FOBt positivity was associated with advanced T-stage (p=0.015), however was not associated with the presence of an elevated SIR (p=0.604). When T-stage, FOBt positivity and the SIR were examined in binary logistic regression analysis, only advanced T-stage (O.R. 2.82, 95% C.I. 1.32 – 6.02, p=0.008) remained significant in predicting those more likely to be anaemic. Conclusions: In this predominantly early stage cohort of screen-detected colorectal cancer, anaemia was uncommon. Its presence was related to both a greater amount of enteric blood loss and an elevated SIR, however these appear to be driven by the stage of the tumour itself. Further work, exploring in more detail the mechanism by which anaemia develops in early stage colorectal cancer is required.

Correlation of pretreatment hemoglobin and platelet counts with clinicopathological features in colorectal cancer in Saudi population

Background/Aims:In Saudi Arabia, colorectal cancers (CRCs) are registered as the second most common cancers. However, no data has been reported about correlation of the severity of the anemia and pretreatment platelets level with clinicopathological features of CRCs. We aimed to evaluate the association between pretreatment hemoglobin and platelets level and the clinicopathological features of CRC patients in Saudi Arabia.Materials and Methods:Between September 2005 and November 2011, One hundred and fifty-four confirmed CRC patients underwent thorough physical examination, blood investigations, endoscopic ultrasonography (EUS), and computed tomography (CT) for staging before surgery. Findings of physical assessment, EUS, CT, and pathological specimens were correlated with pretreatment hemoglobin and platelets levels the Pearson-Kendall tau correlative coefficients.Results:The mean age of cohort was 56.6 years (range: 26-89). Left-sided CRC were predominant (97 patients; 63%). Mean size of primary tumor was 6 cms (1-18) SD ± 3.55. Mean values of hemoglobin, red blood cells, hematocrit, white blood cells, and platelets were 11.9 SD ± 2.3, 35.5 SD ± 5.7, 4.43 × 106/mL SD ± 0.6, 7.67 106/mL SD ± 2.44, and 343 × 103/mL SD ± 164.4, respectively. Pretreatment hemoglobin was inversely correlated with primary tumor size (R: 0.71, R2: 1.55, P = 0.0001) and nodal status (R: 0.02, R2: 0.05, P = 0.01). Right-sided CRC had significantly low pretreatment hemoglobin levels (P = 0.001). Interestingly, pretreatment thrombocytosis was seen only in right-sided CRC (P = 0.0001).Conclusion:Pretreatment anemia and thrombocytosis were found mainly in right-sided CRCs and advanced primary and nodal stages. Pretreatment hemoglobin and thrombocytosis can be considered as useful prognostic markers in CRC patients.

A pattern recognition system for colorectal cancer characterization, based on AIB stained histopathological images

A pattern recognition system for colorectal cancer characterization, based on AIB stained histopathological images

Characterization of colorectal cancer (CRC) in Lynch syndrome (LS) patients with MSH6 or PMS2 mutations.

1555 Background: The majority of LS patients harbor germline mutations in the MLH1 or MSH2 genes. However, ~10% have MSH6 and ~&lt;5% PMS2 mutations. An attenuated form of LS has been suggested in MSH6/PMS2 carriers with decreased CRC risk and older age of disease onset. As recent guidelines suggest that initiation of CRC screening may be delayed in such patients, we characterized our patients with MSH6/PMS2-associated CRC. Methods: We obtained an IRB waiver to identify all LS patients with CRC, defined as the presence of a deleterious germline mutation in a MMR gene, from the Clinical Genetics database at MSKCC. Clinical, pathologic, and genetic features were extracted from medical records and Progeny software. Results: Of 147 LS patients with CRC, 23 had mutations in the MSH6 (n=16, 11%) or PMS2 (n=7, 5%) genes. Mean age at CRC diagnosis was 48.5 yrs (range 32-70) in MSH6 and 40.7 (range 22-57) in PMS2 carriers. 16 (70%) and 5 (22%) were diagnosed at age ≤50 or ≤35, respectively. 4 (17%) had metachronous and 3 (13%) synchronous primary CRCs, and 5 (22%) had additional LS-associated cancer. Although all 23 LS patients met Revised Bethesda guidelines, only 50% of MSH6 and 0 of the PMS2 carriers met Amsterdam I/II criteria (AC). Of 32 independent primary CRCs, 18 (56%) were stage I/II, 9 (28%) stage III, and 1 (3%) stage IV. 9/9 MSH6 and 4/4 PMS2 CRCs had high-frequency microsatellite instability. In MSH6 carriers, 11/13 had absence of MSH6protein expression only on IHC, 1 had inconclusive MSH6 staining, and 1 had absence of both MSH6 &amp; MSH2 proteins. In PMS2carriers, 7/7 had absence of PMS2 on IHC, 2 also had equivocal/focal MLH1 staining. Right-sided CRC was present in 50% and at least 40% had mucinous features. 26/29 (90%) of tumors underwent segmental resection. 6/11 stage II patients received adjuvant chemotherapy including 2 with pT4N0 tumors. With a mean follow-up of 5.6 yrs to date, 1 patient is known to have developed recurrent CRC. Conclusions: Although the majority of MSH6/PMS2 CRC patients do not meet AC, 70% of CRCs were diagnosed at age ≤50, 22% at age ≤35, and 30% had synchronous/metachronous CRCs. These findings have important implications for CRC surveillance and may not support delaying colonoscopy initiation in MSH6/PMS2 LS families.

Correlation of methylation of CpG island in cystathionine beta synthase promoter and clinicopathological features in colorectal cancer

To explore the association between methylation of cystathionine-beta-synthase (CBS) promoter and clinicopathological features in colorectal cancer. Bisulfate sequencing PCR, real-time RT-PCR, and immunohistochemistry were used to investigate the methylation of CpG island in CBS promoter of 95 sporadic colorectal cancers. Software SPSS PASW Statistics was used to analyze the data of the hypermethylation levels in the malignant tissues and the correlation with pathological parameters and clinical outcome. Methylation levels in tumor tissue of patients [(64.9 ± 14.3)%]with colorectal cancer were significantly higher than that in normal tissues[(27.5 ± 13.1)%, P < 0.001]. The CBS mRNA levels in the hypomethylation group (7.22 ± 1.91) were significantly higher than that in the hypermethylation group (2.78 ± 1.12, P < 0.01). Univariate analysis showed that age, pT stage, pN stage, liver metastases, pTNM stage, and CBS hypermethylation level significantly correlated with the survival and recurrence rates of colorectal cancer patients (All P < 0.05). Multivariate analysis showed that CBS hypermethylation level and liver metastasis were independent factors significantly correlated with the recurrence rate and overall survival of the patients (All P < 0.05). Our study indicates that methylation of CpG island in CBS promoter is correlated with the occurrence and progression of colorectal cancer and plays a role in its tumorigenesis. It might serve as a useful marker for early diagnosis, targeted therapy and prediction of prognosis in colorectal cancer.

Su1080 Limited Diagnostic Value of Microsatellite Instability Associated Pathology Features in Colorectal Cancer

Su1080 Limited Diagnostic Value of Microsatellite Instability Associated Pathology Features in Colorectal Cancer

Van-Gogh-like 2 antagonises the canonical WNT pathway and is methylated in colorectal cancers

Background:Aberrant activation of the canonical WNT signaling is a feature of colorectal cancer (CRC). Van-Gogh-like 2 (VANGL2) belongs to the non-canonical WNT pathway whose activation inhibits canonical WNT signaling. In this study, we investigated the role of VANGL2 and its epigenetic regulation in CRC.Methods:Van-Gogh-like 2 expression and promoter methylation after 5-aza-2′-deoxycytidine (5-aza) treatment were evaluated in CRC cells. DNA samples from 418 sporadic CRCs were tested for VANGL2 promoter methylation and microsatellite instability (MSI). Proliferation, colony formation and activation of the WNT pathway were tested in cells after VANGL2 overexpression.Results:Van-Gogh-like 2 mRNA was significantly higher in 5-aza-treated RKO, LOVO and SW48, whereas no differences were found in SW480. Van-Gogh-like 2 was fully methylated in RKO, SW48, HCT116, DLD1 and Caco2; partially methylated in LOVO, LS174T and SW837; and unmethylated in SW480, SW620 and HT29. Higher expression of VANGL2 mRNA was found in the unmethylated cell lines. In CRC specimens (8.93% MSI), methylated VANGL2 was associated with MSI, higher grade, proximal colon location and BRAF mutation. Van-Gogh-like 2 overexpression in SW480 significantly decreased proliferation, colony formation and β-catenin levels.Conclusion:Van-Gogh-like 2 is frequently methylated in MSI-CRCs with BRAF mutation and may act as a tumour suppressor gene, counteracting WNT/β-catenin signaling.

Association of BMP6 Methylation and Expression with Clinicopathological Features in Colorectal Cancer

Association of BMP6 Methylation and Expression with Clinicopathological Features in Colorectal Cancer