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1.  An Evidence-Based Microsimulation Model for Colorectal Cancer: Validation and Application 
The Colorectal Cancer Simulated Population model for Incidence and Natural history (CRC-SPIN) is a new microsimulation model for the natural history of colorectal cancer (CRC) that can be used for comparative effectiveness studies of CRC screening modalities.
CRC-SPIN simulates individual event histories associated with CRC, based on the adenoma-carcinoma sequence: adenoma initiation and growth, development of preclinical invasive CRC, development of clinically detectable CRC, death from CRC, and death from other causes. We present CRC-SPIN structure and parameters, data used for model calibration, and model validation. We also provide basic model outputs to further describe CRC-SPIN, including annual transition probabilities between various disease states and dwell times. We conclude with a simple application which predicts the impact of a one time colonoscopy at age 50 on the incidence of CRC assuming three different operating characteristics for colonoscopy.
CRC-SPIN provides good prediction of both the calibration and validation data. Using CRC-SPIN, we predict that a one time colonoscopy greatly reduces CRC incidence over the subsequent 35 years.
CRC-SPIN is a valuable new tool for combining expert opinion with observational and experimental results to predict the comparative effectiveness of alternative CRC screening modalities.
Microsimulation models are increasingly being used to guide health policy decisions. It is critical that these models be fully described and reviewed in the literature, and that model predictions include measures of precision to allow for appropriate use of model predictions.
PMCID: PMC2919657  PMID: 20647403
comparative effectiveness; screening
2.  Identification of Kininogen-1 as a Serum Biomarker for the Early Detection of Advanced Colorectal Adenoma and Colorectal Cancer 
PLoS ONE  2013;8(7):e70519.
Serum markers represent potential tools for the detection of colorectal cancer (CRC). The aim of this study was to obtain proteomic expression profiles and identify serum markers for the early detection of CRC.
Proteomic profiles of serum samples collected from 35 healthy volunteers, 35 patients with advanced colorectal adenoma (ACA), and 40 patients with CRC were compared using Clinprot technology. Using enzyme-linked immunosorbent assays (ELISAs), 366 sera samples were additionally analyzed, and immunohistochemistry studies of 400 tissues were used to verify the expression of kininogen-1 and its value in the early detection of CRC.
Predicting models were established among the three groups, and kininogen-1 was identified as a potential marker for CRC using Clinprot technology. ELISAs also detected significantly higher serum kininogen-1 levels in ACA and CRC patients compared to controls (P<0.05). Furthermore, the area under the receiver operating characteristic curve (AUC) for serum kininogen-1 in the diagnosis of ACA was 0.635 (P = 0.003), and for serum carcinoembryonic antigen (CEA) was 0.453 (P = 0.358). The sensitivity, specificity, and accuracy of serum kininogen-1 for diagnosing Duke’s stage A and B CRC was 70.13%, 65.88%, and 67.90%, respectively, whereas serum CEA was 38.96%, 85.88%, and 63.58%, respectively. Moreover, immunohistochemistry showed that expression of kininogen-1 was significantly higher in CRC and ACA tissues than in normal mucosa (48.39% vs. 15.58% vs. 0%, P<0.05).
These results suggest that Clinprot technology provides a useful tool for the diagnosis of CRC, and kininogen-1 is a potential serum biomarker for the early detection of advanced colorectal adenoma and CRC.
PMCID: PMC3720899  PMID: 23894665
3.  Detection of Colorectal Cancer by Serum and Tissue Protein Profiling: A Prospective Study in a Population at Risk 
Biomarker Insights  2008;3:375-385.
Colorectal cancer (CRC) is the second most common cause of cancer-related death in Europe and its prognosis is largely dependent on stage at diagnosis. Currently, there are no suitable tumour markers for early detection of CRC. In a retrospective study we previously found discriminative CRC serum protein profiles with surface enhanced laser desorption ionisation—time of flight mass spectrometry (SELDI-TOF MS). We now aimed at prospective validation of these profiles. Additionally, we assessed their applicability for follow-up after surgery and investigated tissue protein profiles of patients with CRC and adenomatous polyps (AP). Serum and tissue samples were collected from patients without known malignancy with an indication for colonoscopy and patients with AP and CRC during colonoscopy. Serum samples of controls (CON; n = 359), patients with AP (n = 177) and CRC (n = 73), as well as tissue samples from AP (n = 52) and CRC (n = 47) were analysed as described previously. Peak intensities were compared by non-parametric testing. Discriminative power of differentially expressed proteins was assessed with support vector machines (SVM). We confirmed the decreased serum levels of apolipoprotein C-1 in CRC in the current population. No differences were observed between CON and AP. Apolipoprotein C-I levels did not change significantly within 1 month post-surgery, although a gradual return to normal levels was observed. Several proteins differed between AP and CRC tissue, among which a peak with similar mass as apolipoprotein C-1. This peak was increased in CRC compared to AP. Although we prospectively validated the serum decrease of apolipoprotein C-1 in CRC, serum protein profiles did not yield SVM classifiers with suitable sensitivity and specificity for classification of our patient groups.
PMCID: PMC2688344  PMID: 19578519
biomarkers; colorectal cancer; SELDI-TOF MS; validation
4.  The Potential Role of ORM2 in the Development of Colorectal Cancer 
PLoS ONE  2012;7(2):e31868.
Colorectal cancer (CRC) is the third most common malignancy in the world. The risk of death is closely correlated to the stage of CRC at the time of primary diagnosis. Therefore, there is a compelling need for the identification of blood biomarkers that can enable early detection of CRC. We used a quantitative proteomic approach with isobaric labeling (iTRAQ) to examine changes in the plasma proteome of 10 patients with CRC compared to healthy volunteers. Enzyme-Linked Immunosorbnent Assay (ELISA) and Western blot were used for further validation. In our quantitative proteomics analysis, we detected 75 human plasma proteins with more than 95% confidence using iTRAQ labeling in conjunction with microQ-TOF MS. 9 up-regulated and 4 down-regulated proteins were observed in the CRC group. The ORM2 level in plasma was confirmed to be significantly elevated in patients suffering from CRC compared with the controls. ORM2 expression in CRC tissues was significantly increased compared with that in corresponding adjacent normal mucous tissues (P<0.001). ITRAQ together with Q-TOF/MS is a sensitive and reproducible technique of quantitative proteomics. Alteration in expression of ORM2 suggests that ORM2 could be used as a potential biomarker in the diagnosis of CRC.
PMCID: PMC3283705  PMID: 22363757
5.  The influence of health literacy on colorectal cancer screening knowledge, beliefs and behavior. 
OBJECTIVE: To determine if health literacy is associated with knowledge of colorectal cancer (CRC) and CRC screening tests, with perceived benefits and barriers to CRC screening, with perceived risk of CRC, with reported self-efficacy for completing CRC screening and with receipt of CRC tests. METHODS: A convenience sample of 99 subjects completed a health literacy assessment, the Rapid Estimate of Adult Literacy in Medicine (REALM) and a structured interview. RESULTS: Limited or inadequate health literacy was significantly associated with less knowledge about CRC and CRC screening and with more reported barriers to completing fecal occult blood testing (FOBT) and colonoscopy in multivariate analysis. Health literacy was not associated with perceived benefits or reported self-efficacy for completing FOBT or colonoscopy, with perceived risk of developing CRC or with completing CRC tests. However, our small sample size limited our power to detect differences. CONCLUSIONS: Patients with limited health literacy have less knowledge about CRC and CRC screening and report more barriers to completing FOBT and colonoscopy. Interventions to improve CRC screening should consider the health literacy of patients, especially when addressing barriers to screening. Future studies are needed to better define the role of health literacy in CRC screening.
PMCID: PMC2574401  PMID: 17987913
6.  Fecal immunochemical test accuracy in average-risk colorectal cancer screening 
AIM: To assess the fecal immunochemical test (FIT) accuracy for colorectal cancer (CRC) and advanced neoplasia (AN) detection in CRC screening.
METHODS: We performed a multicentric, prospective, double blind study of diagnostic tests on asymptomatic average-risk individuals submitted to screening colonoscopy. Two stool samples were collected and the fecal hemoglobin concentration was determined in the first sample (FIT1) and the highest level of both samples (FITmax) using the OC-sensor™. Areas under the curve (AUC) for CRC and AN were calculated. The best FIT1 and FITmax cut-off values for CRC were determined. At this threshold, number needed to scope (NNS) to detect a CRC and an AN and the cost per lesion detected were calculated.
RESULTS: About 779 individuals were included. An AN was found in 97 (12.5%) individuals: a CRC in 5 (0.6%) and an advanced adenoma (≥ 10 mm, villous histology or high grade dysplasia) in 92 (11.9%) subjects. For CRC diagnosis, FIT1 AUC was 0.96 (95%CI: 0.95-0.98) and FITmax AUC was 0.95 (95%CI: 0.93-0.97). For AN, FIT1 and FITmax AUC were similar (0.72, 95%CI: 0.66-0.78 vs 0.73, 95%CI: 0.68-0.79, respectively, P = 0.34). Depending on the number of determinations and the positivity threshold cut-off used sensitivity for AN detection ranged between 28% and 42% and specificity between 91% and 97%. At the best cut-off point for CRC detection (115 ng/mL), the NNS to detect a CRC were 10.2 and 15.8; and the cost per CRC was 1814€ and 2985€ on FIT1 and FITmax strategies respectively. At this threshold the sensitivity, NNS and cost per AN detected were 30%, 1.76, and 306€, in FIT1 strategy, and 36%, 2.26€ and 426€, in FITmax strategy, respectively.
CONCLUSION: Performing two tests does not improve diagnostic accuracy, but increases cost and NNS to detect a lesion.
PMCID: PMC3921527  PMID: 24574776
Colorectal neoplasms; Early detection of cancer; Sensitivity and specificity; Adenoma; Occult blood; Cost-benefit analysis
7.  Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer 
AIM: To evaluate the effect of mitochondrial tumor necrosis factor receptor-associated protein-1 (TRAP-1) on the lymph node metastasis (LNM) in Chinese colorectal cancer (CRC) patients, and develop potential LNM-associated biomarkers for CRC using quantitative real-time polymerase chain reaction (RT-PCR) analysis.
METHODS: Differences in mitochondrial TRAP-1 gene expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed in 96 Chinese colorectal carcinoma samples using quantitative RT-PCR analysis, Western blotting, and confirmed with immunohistochemical assay. The relationship between clinicopathological parameters and potential diagnostic biomarkers was also examined.
RESULTS: TRAP-1 was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by RT-PCR, Western blotting and immunohistochemical assay. The expression of TRAP-1 in two different metastatic potential human colorectal cancer cell lines, LoVo and HT29, was analyzed with Western blotting. The expression level of TRAP-1 was dramatically higher in LoVo than in HT29. Overexpression of TRAP-1 was significantly associated with LNM (90.2% in LNM group vs 22% in non-LNM group, P < 0.001), the advanced tumor node metastasis stage (89.1% in LNM group vs 26.9% in non-LNM group, P < 0.001), the increased 5-year recurrence rate (82.7% in LNM group vs 22.6% in non-LNM group, P < 0.001) and the decreased 5-year overall survival rate (48.4% in LNM vs 83.2% in non-LNM group, P < 0.001). Univariate and multivariate analyses indicated that TRAP-1 expression was an independent prognostic factor for recurrence and survival of CRC patients (Hazard ratio of 2.445 in recurrence, P = 0.017; 2.867 in survival, P = 0.028).
CONCLUSION: Mitochondria TRAP-1 affects the lymph node metastasis in CRC, and may be a potential biomarker for LNM and a prognostic factor in CRC. Over-expression of TRAP-1 is a predictive factor for the poor outcome of colorectal cancer patients.
PMCID: PMC3491605  PMID: 23139614
Colorectal cancer; Lymph node metastasis; Prognosis; Quantitative real-time polymerase chain reaction analysis; Hsp90 family; Mitochondria tumor necrosis factor receptor-associated protein-1
8.  Microsatellite instability among individuals of Hispanic origin with colorectal cancer 
Cancer  2010;116(21):4965-4972.
Though the presence of microsatellite instability (MSI) in patients with colorectal cancer (CRC) may have implications for prognosis, therapy, and family counseling, MSI prevalence is not well described among individuals of Hispanic origin in the United States (US) with CRC.
We conducted a retrospective cohort study employing a hospital-based tumor registry to identify individuals of Hispanic origin diagnosed with CRC. Clinical data and tumor samples were retrieved. Molecular analyses included testing for MSI using a panel of 5 mononucleotide markers (BAT25, BAT26, NR21, NR24 and NR27) in a pentaplex polymerase chain reaction assay, as well as immunohistochemistry for the MMR proteins MLH1, MSH2, MSH6, and PMHS2 on representative tissue.
111 individuals of Hispanic origin with CRC were identified. 41.1% were women, median age was 57 years (IQR:47.1–63.5). 11 (9.8%, 95%CI:4.2–15.6) had MSI CRC, while 14 (14.6%, 95%CI:7.3–21.8) had CRC with≥1 MMR protein abnormality. 10 of 11 individuals with MSI had clinical or molecular characteristics suspicious for Lynch syndrome such as abnormal expression of MSH2 and/or MSH6 (n=7) or age<50 at diagnosis (n=7).
The prevalence of MSI CRC among Hispanic individuals may be similar to other races and ethnicities, but clinical-pathological characteristics, including age at diagnosis and pattern of abnormal MMR protein expression, suggests that sporadic MSI CRC may be less common in individuals of Hispanic origin, and that much MSI observed in this situation may be attributable to Lynch syndrome. Further exploration of the causes of disparate presentations of CRC by ethnicity and race is warranted.
PMCID: PMC2963686  PMID: 20665498
colorectal neoplasms; Hispanic Americans; genomic instability; microsatellite instability; DNA mismatch repair
9.  FOXQ1, a Novel Target of the Wnt Pathway and a New Marker for Activation of Wnt Signaling in Solid Tumors 
PLoS ONE  2013;8(3):e60051.
The forkhead box transcription factor FOXQ1 has been shown to be upregulated in colorectal cancer (CRC) and metastatic breast cancer and involved in tumor development, epithelial-mesenchymal transition and chemoresistance. Yet, its transcriptional regulation is still unknown.
FOXQ1 mRNA and protein expression were analysed in a panel of CRC cell lines, and laser micro-dissected human biopsy samples by qRT-PCR, microarray GeneChip® U133 Plus 2.0 and western blots. FOXQ1 regulation was assayed by chromatin immunoprecipitation and luciferase reporter assays.
FOXQ1 was robustly induced in CRC compared to other tumors, but had no predictive value with regards to grade, metastasis and survival in CRC. Prototype-based gene coexpression and gene set enrichment analysis showed a significant association between FOXQ1 and the Wnt pathway in tumors and cancer cell lines from different tissues. In vitro experiments confirmed, on a molecular level, FOXQ1 as a direct Wnt target. Analysis of known Wnt targets identified FOXQ1 as the most suitable marker for canonical Wnt activation across a wide panel of cell lines derived from different tissues.
Our data show that FOXQ1 is one of the most over-expressed genes in CRC and a direct target of the canonical Wnt pathway. It is a potential new marker for detection of early CRC and Wnt activation in tumors of different origins.
PMCID: PMC3608605  PMID: 23555880
10.  Increased plasma levels of the APC-interacting protein MAPRE1, LRG1 and IGFBP2 preceding a diagnosis of colorectal cancer in women 
Longitudinal blood collections from cohort studies provide the means to search for proteins associated with disease prior to clinical diagnosis. We investigated plasma samples from the Women’s Health Initiative (WHI) cohort to determine quantitative differences in plasma proteins between subjects subsequently diagnosed with colorectal cancer (CRC) and matched controls that remained cancer free during the period of follow-up. Proteomic analysis of WHI samples collected prior to diagnosis of CRC resulted in the identification of six proteins with significantly (p <0.05) elevated concentrations in cases compared to controls. Proteomic analysis of two colorectal cancer cell lines showed 5 of the 6 proteins were produced by cancer cells. MAPRE1, IGFBP2, LRG1 and CEA were individually assayed by enzyme linked immunosorbent assay (ELISA) in 58 pairs of newly diagnosed CRC samples and controls and yielded significant elevations (p <0.05) among cases relative to controls. A combination of these four markers resulted in an ROC with an AUC=0.841 and 57% sensitivity at 95% specificity. This combination rule was tested in an independent set of WHI samples collected within 7 months prior to diagnosis from cases and matched controls resulting in 41% sensitivity at 95% specificity. A panel consisting of CEA, MAPRE1, IGFBP2 and LRG1 has predictive value in pre-diagnostic colorectal cancer plasmas.
PMCID: PMC3419141  PMID: 22277732
colorectal cancer; risk markers; Pre-Diagnostic samples
11.  Race/Ethnicity, Gender, Weight Status, and Colorectal Cancer Screening 
Journal of Obesity  2011;2011:314619.
Background. The literature on colorectal cancer (CRC) screening is contradictory regarding the impact of weight status on CRC screening. This study was intended to determine if CRC screening rates among 2005 National Health Interview Survey (NHIS) respondent racial/ethnic and gender subgroups were influenced by weight status. Methods. Univariable and multivariable logistic regression analyses were performed to determine if CRC screening use differed significantly among obese, overweight, and normal-weight individuals in race/ethnic and gender subgroups. Results. Multivariable analyses showed that CRC screening rates did not differ significantly for individuals within these subgroups who were obese or overweight as compared to their normal-weight peers. Conclusion. Weight status does not contribute to disparities in CRC screening in race/ethnicity and gender subgroups.
PMCID: PMC3236519  PMID: 22187635
12.  Low-serum GTA-446 anti-inflammatory fatty acid levels as a new risk factor for colon cancer 
Gastrointestinal tract acid-446 (GTA-446) is a long-chain polyunsaturated fatty acid present in the serum. A reduction of GTA-446 levels in colorectal cancer (CRC) patients has been reported previously. Our study compared GTA-446 levels in subjects diagnosed with CRC at the time of colonoscopy to the general population. Serum samples and pathology data were collected from 4,923 representative subjects undergoing colonoscopy and from 964 subjects from the general population. Serum GTA-446 levels were determined using a triple-quadrupole tandem mass spectrometry method. A low-serum GTA-446 level was based on the bottom tenth percentile of subjects with low risk based on age (40–49 years old) in the general population. Eighty-six percent of newly diagnosed CRC subjects (87% for stages 0–II and 85% for stages III–IV) showed low-serum GTA-446 levels. A significant increase in the CRC incidence rate with age was observed in subjects with low GTA-446 levels (p = 0.019), but not in subjects with normal levels (p = 0.86). The relative risk of CRC given a low GTA-446 level was the highest for subjects under age 50 (10.1, 95% confidence interval [C.I.] = 6.4–16.4 in the reference population, and 7.7, 95% C.I. = 4.4–14.1 in the colonoscopy population, both p < 0.0001), and declined with age thereafter. The CRC incidence rate in subjects undergoing colonoscopy with low GTA-446 levels was over six times higher than for subjects with normal GTA-446 levels and twice that of subjects with gastrointestinal symptoms. The results show that a low-serum GTA-446 level is a significant risk factor for CRC, and a sensitive predictor of early-stage disease.
PMCID: PMC3675640  PMID: 22696299
colorectal cancer; screening; biomarker; inflammation; fatty acid; GTA-446
13.  Identification of MXRA5 as a novel biomarker in colorectal cancer 
Oncology Letters  2012;5(2):544-548.
In our previous study, significantly high expression levels of matrix-remodeling associated 5 (MXRA5) were identified in fresh-cultured colorectal cancer (CRC) tissues compared with their normal adjacent mucosa by differential secretome analysis. Whether MXRA5 is a potential serum biomarker of CRC has not been evaluated. The aim of this study was to investigate the association between MXRA5 expression and clinicopathological characteristics of CRC patients. The MXRA5 expression levels were determined by quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) in 20 colorectal adenoma tissues, 156 CRC tissues and their corresponding adjacent normal mucosa. Relative quantity (RQ) value and immunoreactive score (IRS) were used for quantitative assessment. The staining for MXRA5 protein was mainly located in the cytoplasm of CRC cells. All CRC tissues were positively stained, with a higher expression rate (IRS>4) of 67% (105/156), and a lower expression rate (IRS≤4) of 33% (51/156). Meanwhile, their corresponding normal tissues exhibited little positive staining; the higher expression rate was 0% (0/156) and the lower expression rate was 25% (16/156). Additionally, more than half of the adenoma tissues were positively stained; the higher expression rate was 15% (3/20) and the lower expression rate was 50% (10/20). The MXRA5 protein positive staining rates were significantly correlated with the lesion sites (colon vs. rectum, 76 vs. 59%), TNM staging (I+II vs. III+IV, 56 vs. 73%) and metastasis (present vs. absent; 76 vs. 61%) with the most high positive staining rate observable in omental metastasis (82%). However, MXRA5 mRNA expression levels showed no significant differences between CRC tissues and their corresponding normal tissues, and no significant correlation between IRS and corresponding RQ value was observed. In this study, we present the first evaluation of MXRA5 protein expression in CRC tissue. Our results revealed that MXRA5 protein is aberrantly expressed in CRC tissues, and has potential value in early detection of CRC and prediction of omental metastasis.
PMCID: PMC3573052  PMID: 23420087
MXRA5; colorectal cancer; proteomics; omental metastasis
14.  How should individuals with a false-positive fecal occult blood test for colorectal cancer be managed? A decision analysis 
Several industrialized nations recommend fecal occult blood testing (FOBT) to screen for colorectal cancer (CRC), but corresponding screening guidelines do not specify how individuals with a prior false positive FOBT result (fpFOBT) should be managed in terms of subsequent CRC screening. Accordingly, we conducted a decision analysis to compare different strategies for managing such individuals.
We used a previously-developed CRC microsimulation model, SimCRC, to calculate life-years and the lifetime number of colonoscopies (as a measure of required resources) for a cohort of 50-year-olds to whom FOBT-based CRC screening is offered annually from age 50 to 75. We compared three management strategies for individuals with a prior fpFOBT: 1) resume screening in 10 years with 10-yearly colonoscopy (SwitchCol_long); 2) resume screening in 1 year with annual FOBT (ContinueFOBT_Short); and 3) resume screening in 10 years (i.e., the recommended interval following a negative colonscopy) with annual FOBT (ContinueFOBT_long). We performed sensitivity analyses on various parameters and assumptions.
When using different management strategies for individuals with a prior fpFOBT the variation in the number of life-years gained relative to no screening was less than 2%, while the variation in the lifetime number of colonoscopies was 23% (percentages are calculated as the maximum difference across strategies divided by the lowest number across strategies). The ContinueFOBT_long strategy showed the lowest lifetime number of colonoscopies per life-year gained even when key assumptions were varied.
In conclusion, the ContinueFOBT_long strategy was advantageous regarding both clinical benefit and required resources. Specifying an appropriate management strategy for individuals with a prior fpFOBT may substantially reduce required resources within a FOBT-based CRC screening program without limiting its effectiveness.
PMCID: PMC3693764  PMID: 22307927
colorectal cancer; screening; fecal occult blood
15.  Prevalence of screening in patients newly diagnosed with colorectal cancer in Ontario 
The primary objective was to determine the proportion of individuals with a new diagnosis of colorectal cancer (CRC) in Ontario in whom the cancer was screen detected. The secondary objectives were to determine the cancer stage at diagnosis and the indications for the procedure in patients who received their first colonoscopy.
Individuals admitted to a hospital with a new diagnosis of CRC were randomly selected after stratifying by hospital type (teaching or community). The Canadian Institute for Health Information’s Discharge Abstract Database was used to identify individuals with a first diagnosis of CRC during calendar year (CY) 2000, and Ontario Health Insurance Plan data were used to identify people 50 to 74 years of age who had their first colonoscopy during CY 2000. Up to 20 individuals were selected for each group (CRC or colonoscopy) in each of seven randomly selected community hospitals and three randomly selected teaching hospitals. Data were abstracted from the hospital charts.
The hospital charts of 152 patients with a new diagnosis of CRC were examined. Of the 133 patients in whom screening status could be determined, eight had screen-detected cancers (6.0%). Of the 99 patients (65% of the sample) in whom stage could be determined, 43 (43.4%) had advanced disease (tumour-node-metastasis stage III or IV) at diagnosis. The hospital charts of 184 patients who underwent their first colonoscopy were examined. Of the 175 patients in whom the indication for colonoscopy could be determined, 45 underwent the procedure for screening purposes, 10 were for diagnostic workup of anemia and 120 for evaluation of symptoms.
The low proportion (6%) of screen-detected CRC and the high proportion of patients (43.4%) with advanced disease at diagnosis reflect the lack of an organized screening program.
PMCID: PMC2658572  PMID: 18080051
Cancer stage; Colorectal cancer; Screening
16.  Individualizing Colonoscopy Screening by Gender and Race 
Gastrointestinal endoscopy  2009;70(1):96-10924.
There is increasing discussion whether colorectal cancer (CRC) screening guidelines should be individualized by gender and race.
To determine individualized colonoscopic screening guidelines by gender and race for the average-risk population and to compare the cost-effectiveness of this approach to that of uniform guidelines for all.
We used the MISCAN-Colon microsimulation model to estimate life-expectancy and lifetime CRC screening and treatment costs in a US cohort of black and white men and women at average risk for CRC. We compared the base case strategy of no screening and 3 competing colonoscopy strategies: (1) the currently recommended “uniform 10-yearly colonoscopy from age 50”, (2) with a shorter interval “uniform 8- yearly colonoscopy from age 51”, and (3) “individualized screening according to gender and race”.
The base case strategy of no screening was the least expensive, yet least effective. The uniform 10-yearly colonoscopy strategy was dominated. The uniform 8- yearly colonoscopy and individualized strategies both increased life-expectancy by 0.0433-0.0435 years per individual at a cost of $15,565 per life-year gained. In the individualized strategy, African Americans began screening 6 years earlier with a 1 year shorter interval compared to whites. The individualized policies were essentially the same for men and women, because the higher CRC risk in men is offset by their shorter life-expectancy. The results were robust for changes in model assumptions.
The improvements in costs and effects of individualizing on a population level were only marginal. Individualized guidelines, however, could contribute to decreasing disparities between African Americans and whites. The acceptability and feasibility of individualized guidelines should therefore be explored.
PMCID: PMC2805960  PMID: 19467539
17.  High expression level and nuclear localization of Sam68 are associated with progression and poor prognosis in colorectal cancer 
BMC Gastroenterology  2013;13:126.
Src-associated in mitosis (Sam68; 68 kDa) has been implicated in the oncogenesis and progression of several human cancers. The aim of this study was to investigate the clinicopathologic significance of Sam68 expression and its subcellular localization in colorectal cancer (CRC).
Sam68 expression was examined in CRC cell lines, nine matched CRC tissues and adjacent noncancerous tissues using reverse transcription (RT)-PCR, quantitative RT-PCR and Western blotting. Sam68 protein expression and localization were determined in 224 paraffin-embedded archived CRC samples using immunohistochemistry. Statistical analyses were applied to evaluate the clinicopathologic significance.
Sam68 was upregulated in CRC cell lines and CRC, as compared with normal tissues; high Sam68 expression was detected in 120/224 (53.6%) of the CRC tissues. High Sam68 expression correlated significantly with poor differentiation (P = 0.033), advanced T stage (P < 0.001), N stage (P = 0.023) and distant metastasis (P = 0.033). Sam68 nuclear localization correlated significantly with poor differentiation (P = 0.002) and T stage (P =0.021). Patients with high Sam68 expression or Sam68 nuclear localization had poorer overall survival than patients with low Sam68 expression or Sam68 cytoplasmic localization. Patients with high Sam68 expression had a higher risk of recurrence than those with low Sam68 expression.
Overexpression of Sam68 correlated highly with cancer progression and poor differentiation in CRC. High Sam68 expression and Sam68 nuclear localization were associated with poorer overall survival.
PMCID: PMC3751151  PMID: 23937454
Sam68; Biomarker; Prognosis; Colorectal cancer
18.  Detection of serological biomarkers by proximity extension assay for detection of colorectal neoplasias in symptomatic individuals 
Although the potential of biomarkers to aid in early detection of colorectal cancer (CRC) is recognized and numerous biomarker candidates have been reported in the literature, to date only few molecular markers have been approved for daily clinical use.
In order to improve the translation of biomarkers from the bench to clinical practice we initiated a biomarker study focusing on a novel technique, the proximity extension assay, with multiplexing capability and the possible additive effect obtained from biomarker panels. We performed a screening of 74 different biomarkers in plasma derived from a case–control sample set consisting of symptomatic individuals representing CRC patients, patients with adenoma, patients with non-neoplastic large bowel diseases and healthy individuals.
After statistical evaluation we found 12 significant indicators of CRC and the receiver operating characteristic (ROC) curve of Carcinoembryonic antigen (CEA), Transferrin Receptor-1 (TFRC), Macrophage migration inhibitory factor (MIF), Osteopontin (OPN/SPP1) and cancer antigen 242 (CA242) showed additive effect. This biomarker panel identified CRC patients with a sensitivity of 56% at 90% specificity and thus the performance is sufficiently high to further investigate this combination of five proteins as serological biomarkers for detection of CRC. Furthermore, when applying the indicators to identify early-stage CRC a combination of CEA, TFRC and CA242 resulted in a ROC curve with an area under the curve of 0.861.
Five plasma protein biomarkers were found to be potential CRC discriminators and three of these were additionally found to be discriminators of early-stage CRC. These explorative data in symptomatic individuals demonstrates the feasibility of the multiplex proximity extension assay for screening of potential serological protein biomarkers and warrants independent analyses in a larger sample cohort, including asymptomatic individuals, to further validate the performances of our CRC biomarker panel.
PMCID: PMC3827929  PMID: 24107468
Colorectal cancer; Plasma; Biomarkers; Proximity ligation assay; Proximity extension assay
19.  Faecal immunochemical test accuracy in patients referred for surveillance colonoscopy: a multi-centre cohort study 
BMC Gastroenterology  2012;12:94.
Given the increasing burden on colonoscopy capacity, it has been suggested that faecal immunochemical test (FIT) results could guide surveillance colonoscopy intervals. Against this background, we have evaluated the test accuracy of single and double FIT sampling to detect colorectal cancer (CRC) and/or advanced adenomas in an asymptomatic colonoscopy-controlled high-risk population.
Cohort study of asymptomatic high-risk patients (personal history of adenomas/CRC or family history of CRC), who provided one or two FITs before elective colonoscopy. Test accuracy of FIT for detection of CRC and advanced adenomas was determined (cut-off level 50 ng/ml).
1,041 patients provided a FIT (516 personal history of adenomas, 172 personal history of CRC and 353 family history of CRC). Five CRCs (0.5%) and 101 advanced adenomas (9.7%) were detected by colonoscopy. Single FIT sampling resulted in a sensitivity, specificity, PPV and NPV for CRC of 80%, 89%, 3% and 99.9%, respectively, and for advanced adenoma of 28%, 91%, 24% and 92%, respectively. Double FIT sampling did not result in a significantly higher sensitivity for advanced neoplasia. Simulation of multiple screening rounds indicated that sensitivity of FIT for advanced adenoma could reach 81% after 5 screening rounds.
In once-only FIT sampling before surveillance colonoscopy, 70% of advanced neoplasia were missed. A simulation approach indicates that multiple screening rounds may be more promising in detecting advanced neoplasia and could potentially alleviate endoscopic burden.
PMCID: PMC3444435  PMID: 22828158
Colorectal cancer; Faecal immunochemical test (FIT); Surveillance; Advanced adenoma; Sensitivity
20.  Serum Peptidome Patterns of Colorectal Cancer Based on Magnetic Bead Separation and MALDI-TOF Mass Spectrometry Analysis 
Background. Colorectal cancer (CRC) is one of the most common cancers in the world, identification of biomarkers for early detection of CRC represents a relevant target. The present study aims to determine serum peptidome patterns for CRC diagnosis. Methods. The present work focused on serum proteomic analysis of 32 health volunteers and 38 CRC by ClinProt Kit combined with mass spectrometry. This approach allowed the construction of a peptide patterns able to differentiate the studied populations. An independent group of serum (including 33 health volunteers, 34 CRC, 16 colorectal adenoma, 36 esophageal carcinoma, and 31 gastric carcinoma samples) was used to verify the diagnostic and differential diagnostic capability of the peptidome patterns blindly. An immunoassay method was used to determine serum CEA of CRC and controls. Results. A quick classifier algorithm was used to construct the peptidome patterns for identification of CRC from controls. Two of the identified peaks at m/z 741 and 7772 were used to construct peptidome patterns, achieving an accuracy close to 100% (>CEA, P < 0.05). Furthermore, the peptidome patterns could differentiate validation group with high accuracy. Conclusions. These results suggest that the ClinProt Kit combined with mass spectrometry yields significantly higher accuracy for the diagnosis and differential diagnosis of CRC.
PMCID: PMC3469310  PMID: 23091368
21.  The diagnostic value of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) determination in the sera of colorectal adenoma and cancer patients 
Tumor cells, including colorectal cancer (CRC), are able to produce and release matrix metalloproteinase 9 (MMP-9) which is involved in tumor invasion and metastasis. Natural tissue inhibitors of matrix metalloproteinases (TIMPs) regulate activity of MMPs and stimulate tumor growth and malignant transformation. The aim of the present study was to compare the clinical significance of serum MMP-9 with TIMP-1 in the diagnosis of CRC patients and in the differentiation between colorectal adenoma (CA) and cancer.
Serum MMP-9 and TIMP-1 were measured in 75 CRC patients, 35 CA, and 70 healthy subjects using enzyme-linked immunosorbent assay. Concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were determined by microparticle enzyme immunoassay.
Serum levels of all proteins tested were significantly higher in CRC patients than in healthy subjects. Additionally, serum TIMP-1 was significantly higher in patients with CRC than in CA patients. Concentrations of TIMP-1 correlated with tumor stage, nodal involvement, presence of distant metastases, patients' survival, and tumor resectability. Diagnostic sensitivity of TIMP-1 was higher (61%) than those of other biomarkers (MMP-9, 55%; CEA, 39%; CA 19-9, 11%), and increased in combined use with MMP-9 (75%) or CEA (73%). The areas under receiver operating characteristic curves of TIMP-1 were larger than those of MMP-9.
Our findings suggest better usefulness of serum TIMP-1 than MMP-9 in the diagnosis of CRC, especially in the assessment of Duke's classification of tumor stage, survival of cancer patients, resectability of tumor, and in the differentiation between CA and cancer.
PMCID: PMC2928442  PMID: 20556397
Colorectal cancer; Colorectal adenoma; MMP-9; TIMP-1; Tumor markers
22.  Evaluation of specific fecal protein biochips for the diagnosis of colorectal cancer 
AIM: To develop and initially test a potential fecal protein biochip for the screening of colorectal cancer (CRC).
METHODS: Fecal protein from 20 colorectal cancer patients and 20 healthy controls were extracted from all of the fecal samples and screened for proteomic differences using a Biotin label-based protein array. Candidate proteins were then verified by ELISA. Finally, we will select out the significant protein and a seven-target multiplex fecal protein biochip was generated and tested for 20 fecal samples to determine the effectiveness of the biochip on identifying CRC. And the value of the protein biochip would be discussed.
RESULTS: After tested by protein biochip of the fecal protein from 20 colorectal cancer patients and 20 healthy controls and levels of calprotectin, M2-pyruvatekinase, angiopoietin-2, fibroblast growth factor-23 (FGF-23), proteins of the matrix metalloproteinase, thrombopoietin (TPO) and interleukin-13 (IL-13) were significantly different between CRC and healthy controls. The sensitivity of all the seven proteins combined was 0.7, specificity was 0.4, and area under the receiver operating characteristics was 0.729. The most promising combinations of test proteins were FGF-23, TPO, and IL-13, reaching a sensitivity of 0.7 and a specificity of 0.7. The combination of FGF-23 and TPO scored highest with sensitivity of 0.7 and specificity of 0.8. Its mean that the combination of FGF-23 and TPO has the highest value for the diagnosis of CRC in our study.
CONCLUSION: A protein biochip composed of proteins found to be elevated in the feces of colorectal cancer patients has great potential as a noninvasive diagnostic for colorectal cancer. The addition of new protein biomarkers and technologies, as they are discovered, is an excellent avenue of future research.
PMCID: PMC3921516  PMID: 24574808
Protein biochip; Feces; Colorectal cancer; Fibroblast growth factor-23; Thrombopoietin
23.  Identification of Phospholipid Scramblase 1 as a Biomarker and Determination of Its Prognostic Value for Colorectal Cancer 
Molecular Medicine  2010;17(1-2):41-47.
The purpose of this study was to examine the expression of phospholipid scramblase 1 (PLSCR1) in tumor tissues and plasma specimens of patients with colorectal cancer (CRC), as well as analyze its association with clinical parameters. The expression levels of PLSCR1 protein in 104 matched CRC and adjacent normal tissue sections and 50 pairs of CRC tissue blocks were determined by use of immunohistochemical and Western blot analyses, respectively. To evaluate the diagnostic potential of PLSCR1, the plasma levels of PLSCR1 were investigated in 111 additional subjects (59 CRC patients and 52 healthy controls) by Western blot. PLSCR1 was overexpressed in malignant adenocarcinoma tissues compared with normal colorectal mucosa (P < 0.001). In addition, the plasma level of PLSCR1 was not only significantly elevated in CRC patients compared with healthy individuals (P < 0.001), but it was also substantially increased in early stage CRC (P < 0.001). Importantly, the overall sensitivity and specificity of PLSCR1 for CRC detection were 80% and 59.6%, respectively. The area under the ROC curve of PLSCR1 for CRC diagnosis is 0.75, which increases to 0.8 if combined with the measurement of carcinoembryonic antigen. Univariate analysis with the Cox regression model revealed that elevated PLSCR1 expression indicated a poor prognosis for CRC. This study showed that PLSCR1 protein levels were significantly elevated in both the cancer tissue and plasma of CRC patients. Moreover, the plasma levels of PLSCR1 were significantly elevated in patients with early stage CRC compared with healthy individuals, suggesting that PLSCR1 might be used as a noninvasive serological diagnostic and prognostic biomarker for CRC.
PMCID: PMC3022977  PMID: 20927484
24.  Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer 
BMC Cancer  2009;9:374.
MicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis.
The expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context.
MiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in CRC provide a basis for understanding the functional role of miRNAs in cancer.
PMCID: PMC2770572  PMID: 19843336
25.  Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression 
BMC Cancer  2011;11:195.
Earlier studies have reported the production of histamine in colorectal cancers (CRCs). The effect of histamine is largely determined locally by the histamine receptor expression pattern. Recent evidence suggests that the expression level of histamine receptor H4 (HRH4) is abnormal in colorectal cancer tissues. However, the role of HRH4 in CRC progression and its clinical relevance is not well understood. The aim of this study is to evaluate the clinical and molecular phenotypes of colorectal tumors with abnormal HRH4 expression.
Immunoblotting, real-time PCR, immunofluorescence and immunohistochemistry assays were adopted to examine HRH4 expression in case-matched CRC samples (n = 107) and adjacent normal tissues (ANTs). To assess the functions of HRH4 in CRC cells, we established stable HRH4-transfected colorectal cells and examined cell proliferation, colony formation, cell cycle and apoptosis in these cells.
The protein levels of HRH4 were reduced in most of the human CRC samples regardless of grade or Dukes classification. mRNA levels of HRH4 were also reduced in both early-stage and advanced CRC samples. In vitro studies showed that HRH4 over-expression caused growth arrest and induced expression of cell cycle proteins in CRC cells upon exposure to histamine through a cAMP -dependent pathway. Furthermore, HRH4 stimulation promoted the 5-Fu-induced cell apoptosis in HRH4-positive colorectal cells.
The results from the current study supported previous findings of HRH4 abnormalities in CRCs. Expression levels of HRH4 could influence the histamine-mediated growth regulation in CRC cells. These findings suggested a potential role of abnormal HRH4 expression in the progression of CRCs and provided some new clues for the application of HRH4-specific agonist or antagonist in the molecular therapy of CRCs.
PMCID: PMC3128004  PMID: 21609450

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