Group Of Colorectal Cancer Patients Research Articles

The implication of BRAF mutation in advanced colorectal cancer

BackgroundAdvanced colorectal cancer (CRC) is frequently a lethal disease. Mutations in the BRAF gene is a key driver in CRC pathogenesis and confers a poor prognosis. To date, Irish data on this molecular subtype of CRC is lacking.AimsOur aim was to compare the natural history of Irish patients with BRAF (BRAFMUT) metastatic CRC with a control group of metastatic CRC patients without BRAF mutation (BRAFWT wild- type).MethodA retrospective observational analysis of advanced CRC patients with known BRAFMUT was conducted by chart review. BRAFMUT patients were identified from the Cork University Hospital (CUH) histopathology database. Controls with known BRAFWT were randomly selected from the database. Demographic characteristics and clinicopathological data were recorded. Survival was assessed with Kaplan–Meier curve/Cox proportional hazard models.ResultsTwenty patients with BRAFMUT and 36 with BRAFWT were studied. BRAFMUT were more likely female (75% vs 33%, p = 0.007) and right-sided (65% vs 31.4%, p = 0.033). Median overall survival was lower in BRAFMUT group (17.3 months (95% CI 0–40.8)) compared to patients with BRAFWT (median survival not reached, log rank p = 0.001). On multivariate analysis, BRAFMUT was independently associated with an increased risk of mortality (HR 12.76 (95% CI 3.15–51.7), p < 0.001).ConclusionBRAFMUT advanced colorectal cancer was associated with significantly reduced overall survival in this Irish CRC population. Knowledge of mutation status should now be considered standard of care and should dictate management. Surgeons should be aware of this genetic signature as the natural history of the disease may mitigate against an aggressive surgical strategy. A prospective study should be conducted to further corroborate these findings.

Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression

SummaryInnate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1+ ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC.

Differential expression of long noncoding RNAs in patients with metastatic and nonmetastatic colorectal cancer.

e15023 Background: Long non-coding RNAs (lncRNA) play an important role in many biological processes, and their dysregulation can lead to various diseases, including colorectal cancer (CRC). In recent years, interactions between lncRNA, miRNA and mRNAs in development of CRC have attracted more and more attention. However, the currently obtained data on the complex regulatory interactions between lncRNA and microRNA during metastasis in patients with CRC are fragmentary, often contradictory and obtained on samples that are not significant in size. Therefore, the aim of the study was to analyze the features of lncRNA expression in CRC patients without metastases, with lymph nodes metastases and with liver metastases. Methods: The study included 200 patients with colon adenocarcinoma. The patients were divided into 3 groups: without metastases (T2N0MO, group 1, n = 100), with lymph node metastases (T2-3N1-2M0, group 2, n = 60) and with liver metastases (T3N2M1-2, group 3, n = 40). RNA isolation was performed by guanidine-thiocyanate-phenol-chloroform extraction. The lncRNA list was generated based on bioinformatic analysis. The relative expression of 20 lncRNAs (NEAT1, HELLPAR, AP000766.1, LINC00265, MIRLET7BHG, OLMALINC, AC245884.8, MEOX2-AS1, MEG3, NORAD, HCG11, WASIR2, AC005332.7, PURLN, OIP5-AS1, SNHG14, TUG1, XIST, MALAT1, FAM66E) was evaluated by RT-qPCR method. Differences were assessed using the Mann-Whitney test, and the Bonferroni correction was used to correct multiple comparisons. Results: Differential expression of 5 lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR) was found between CRC patients without metastases and patients with metastases to lymph nodes and liver. Thus, in group 1, expressions of MALAT1, TUG1 and HELLPAR were lower by 2.5, 4.0 and 5.5 times (p &lt; 0.005) than in combined group of patients with metastases to lymph nodes and liver, and XIST and LINC00265 expressions were higher by 2.2 and 3.4 times (p &lt; 0.05), respectively. Differential expression of 2 lncRNA (NORAD, WASIR2) was also found between group 2 and group 3. The NORAD expression in patients in group 3 was 5.5 times (p &lt; 0.05) lower than in patients in group 2, and WASIR2 expression, on the contrary, was 2.5 times (p &lt; 0.05) higher in patients in group 3. Conclusions: Thus, differential expression of lncRNA (MALAT1, TUG1, XIST, LINC00265, HELLPAR, NORAD and WASIR2), associated with regulation of proliferation and invasive ability of tumor cells, was found in 3 groups of CRC patients.

Current and Prospective Methods for Assessing Anti-Tumor Immunity in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the deadliest malignancies worldwide despite recent progress in treatment strategies. Though immune checkpoint inhibition has proven effective for a number of other tumors, it offers benefits in only a small group of CRC patients with high microsatellite instability. In general, heterogenous cell groups in the tumor microenvironment are considered as the major barrier for unveiling the causes of low immune response. Therefore, deconvolution of cellular components in highly heterogeneous microenvironments is crucial for understanding the immune contexture of cancer. In this review, we assimilate current knowledge and recent studies examining anti-tumor immunity in CRC. We also discuss the utilization of novel immune contexture assessment methods that have not been used in CRC research to date.

Correlation between KRAS, NRAS and BRAF mutations and tumor localizations in patients with primary and metastatic colorectal cancer.

IntroductionDetection of abnormalities in the KRAS, NRAS and BRAF genes is extremely important for proper qualification of colorectal cancer (CRC) patients for therapy with anti-EGFR (epidermal growth factor receptor) monoclonal antibodies. However, data about prevalence of mutations in these genes, in different localizations of CRC tumors, are limited.Material and methodsWe examined the frequency of mutations in the KRAS, NRAS and BRAF genes in 500 Caucasian CRC patients (200 women and 300 men, median age 66 years). DNA was isolated from formalin-fixed, paraffin-embedded (FFPE) tissues using a Qiagen QIAamp DNA FFPE-kit. Analysis of mutations was carried out using the KRAS/BRAF, NRAS and BRAF Mutation Analysis Kit for Real-Time PCR (EntroGen) with the Cobas 480 real-time PCR apparatus (Roche Diagnostics).ResultsKRAS mutations were detected in 190 (38%) patients, NRAS mutations in 20 (4%) patients, and BRAF mutations in 24 (4.8%) patients. There were no associations between age of CRC patients and frequency of KRAS, NRAS and BRAF gene mutations. These mutations were significantly more often diagnosed in women (55.5%) than in men (41%, p < 0.005). Tumors of the rectum and sigmoideum were the most often observed in both groups of CRC patients – with and without KRAS, NRAS and BRAF gene mutations. However, transverse colon, ascending colon and cecum cancers were the most often affected by mutations.ConclusionsOur study showed that the occurrence of mutations in the KRAS, NRAS and BRAF genes is not accidental and depends on the location of CRC tumors.

Glycoproteomic Analysis Reveals Aberrant Expression of Complement C9 and Fibronectin in the Plasma of Patients with Colorectal Cancer.

Colorectal cancer (CRC) is a major cause of cancer mortality. Currently used CRC biomarkers provide insufficient sensitivity and specificity; therefore, novel biomarkers are needed to improve the CRC detection. Label-free quantitative proteomics were used to identify and compare glycoproteins, enriched by wheat germ agglutinin, from plasma of CRC patients and age-matched healthy controls. Among 189 identified glycoproteins, the levels of 7 and 15 glycoproteins were significantly altered in the non-metastatic and metastatic CRC groups, respectively. Protein-protein interaction analysis revealed that they were predominantly involved in immune responses, complement pathways, wound healing and coagulation. Of these, the levels of complement C9 (C9) was increased and fibronectin (FN1) was decreased in both CRC states in comparison to those of the healthy controls. Moreover, their levels detected by immunoblotting were validated in another independent cohort and the results were consistent with in the study cohort. Combination of CEA, a commercial CRC biomarker, with C9 and FN1 showed better diagnostic performance. Interestingly, predominant glycoforms associated with acetylneuraminic acid were obviously detected in alpha-2 macroglobulin, haptoglobin, alpha-1-acid glycoprotein 1, and complement C4-A of CRC patient groups. This glycoproteomic approach provides invaluable information of plasma proteome profiles of CRC patients and identification of CRC biomarker candidates.

Abstract PR11: Racial differences in characteristics of early- vs. late-onset colorectal cancer among veterans

Abstract Introduction: Colorectal cancer (CRC) accounts for approximately 8% of annual cancer cases in the Veterans Health Administration. While CRC incidence is decreasing, evidence suggests that the incidence among the subset of patients diagnosed before the age of 50 is increasing. The purpose of this work is to compare the clinical and demographic characteristics of veterans with early-onset CRC (age at diagnosis &amp;lt;50; EOC) and late-onset CRC (age at diagnosis ≥50; LOC) and assess racial differences within both groups. Methods: We conducted a retrospective analysis of national cohort data in the Veterans Affairs Central Cancer Registry on patients diagnosed with CRC between 2001 and 2011. Descriptive statistics (frequencies, medians) were used to compare characteristics among EOC and LOC patients and evaluate black-white differences within both groups of CRC patients. Results: In this cohort of 31,435 patients, 3% (N=966) had EOC, and this proportion was consistent each year. Statistically significant differences between EOC and LOC were noted for race, stage, and tumor location (all p&amp;lt;0.0001). The black/white race distribution was 33%/64% in EOC and 17%/80% in LOC. For stage, 56% of EOC and 44% of LOC were stage III/IV. Regarding tumor location, 39% of EOC was rectum whereas 30% of LOC was rectum. 5-year overall survival (OS) was 58% in EOC and 50% in LOC (p&amp;lt;0.0001); however, no difference in CRC-specific survival was noted (72% vs 74%, p=.13). We also observed significant differences by race when comparing demographic and clinical characteristics within EOC and LOC. Race-specific results for EOC patients were as follows: Median age was 46 for both blacks and whites; the proportion of blacks diagnosed with Stage III/IV disease was 51% compared to 58% of whites (p=0.001); tumor location was rectum for 31% of blacks and 43% of whites (p=0.0006); and overall and CRC-specific survival rates were similar for blacks and whites. The following was observed among patients with LOC: Blacks were slightly younger than whites (median age 66 vs 69, respectively); stage III/IV disease was noted for 47% of blacks and 43% of whites (p&amp;lt;0.0001); 24% of blacks and 31% of whites had rectum tumor location (p&amp;lt;0.0001); and overall and CRC-specific survival rates were lower among blacks compared to whites. Conclusion: Although we did not find an increasing proportion of EOC over time, EOC was more common in blacks than whites and more common in the distal large bowel. EOC in blacks, however, was more commonly proximal, had less advanced stage at diagnosis but similar survival compared to whites. EOC has distinct clinical characteristics in blacks that may reflect differences in molecular etiology. Our findings emphasize the importance of distinguishing between EOC and LOC to better understand the unique characteristics of early-onset disease and how they might inform prevention and early detection efforts. This abstract is also being presented as Poster C116. Citation Format: Monalesia Chapman, Christina D. Williams, Thomas Ivey Redding, Robin Bartlett, Neeta Chawla, Dawn Provenzale, Michael J. Kelley. Racial differences in characteristics of early- vs. late-onset colorectal cancer among veterans [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr PR11.

Diagnosed with a common cancer at an unusual age: causal attributions of survivors of adolescent and young adult colorectal cancer.

Insight into the causes of colorectal cancer (CRC) in adolescent and young adult (AYA) patients is limited. Without definitive information, patients often shape their own beliefs on the cause of their illness, developing causal attributions. This study aims to examine the causal attributions of CRC in AYA patients, compare these with middle-aged and older adults CRC patient groups and explore the association between causal attributions and psychological distress. Two cross-sectional questionnaire studies were conducted among CRC survivors diagnosed between 1998 and 2007 using the population-based PROFILES registry. Three groups were defined by age at diagnosis: AYA (18-39years; n = 67), middle-aged (40-70years; n = 1993) and older adult survivors (70+ years; n = 1922). Causal attributions were assessed in a single free-text item from the Brief Illness Perception Questionnaire and psychological distress measured by the Hospital Anxiety and Depression Scale. AYA survivors most often attributed their CRC to heredity (36.4%), lifestyle (14.5%) and chance (10.9%). AYA survivors attributed their CRC to these causes more frequently than middle-aged and older adult CRC survivors. AYA survivors who attributed their CRC to causes out of their control (chance, heredity) showed significantly lower mean scores on anxiety (4.3 vs. 5.6; p < 0.01) compared to AYAs who reported causes within their control (lifestyle, stress). No significant difference was found for depression. AYA patients with CRC may benefit from in-depth discussion about the lack of known (biological) causes and how this does not directly imply a lifestyle or stress cause.

Pediatric Colorectal Cancer: A Heterogenous Entity.

Colorectal cancer (CRC) is extremely rare in pediatric age. A poor outcome has been reported. We aimed to characterize a group of pediatric CRC patients. All patients with CRC below 18 years old registered in our Familial Cancer Risk Clinic (2002-2016) were included. Clinical and histologic features were evaluated. Germline mutations, microsatellite instability, and DNA mismatch repair proteins expression were analyzed. Five patients were included (3 males; mean age at diagnosis: 14.2 years (range, 9 to 17 y) and 4/5 had family history of cancer in second-degree relatives. With a maximum follow-up of 5.6 years, 2/5 patients died after 10 and 24 months, and 1 recurred after 15 months. All tumors were ≥pT3N2 and 3/5 presented signet ring cells/mucinous histology, corresponding to cases with stronger family history of cancer. Nevertheless, all CRCs analyzed (n=4) were microsatellite stable and/or expressed all mismatch repair proteins. Loss of heterozygosity for the 3 Bethesda dinucleotide markers was detected in 1/3 informative CRCs. A likely pathogenic germline MSH2 mutation was identified in only 1 patient. Pediatric CRC presented advanced disease and poor prognosis. These tumors had distinct histologic and molecular presentations, resembling features from different carcinogenic pathways, thus suggesting a heterogenous nature.

Serum levels of zinc, copper, selenium and glutathione peroxidase in the different groups of colorectal cancer patients.

Background:Colorectal cancer (CRC) is considered the fourth type of cancer that causes death worldwide. Changes in the levels of zinc (Zn), copper (Cu), and selenium (Se) as well as low glutathione peroxidase (GPx) activity can lead to CRC and this study was aimed to evaluate their possible use as diagnostic markers.Methods:CRC patients (n=90) were divided into three groups; newly diagnosed, before surgery, and after surgery. These groups were compared to healthy subjects (n=30); the mean age ±SD was 50.63±9.26 and 49.97±10.85 for CRC patients and healthy subjects, respectively. Biochemical study for serum levels of Zn and Cu was measured by FAAS, Se was measured by HGAAS, and ELISA for GPx.Results:Zn, Cu, Se and GPx were significantly lower in all CRC patient groups, except for the after surgery group which showed no differences for Zn and GPx as compared to the healthy subjects. Positive correlations were found between Se and Zn and between Se and GPx (r=0.71, r=0.42; P<0.01, respectively) in all CRC patient groups. A receiver operating characteristic (ROC) curve analysis was applied for the newly diagnostic group showing all the parameters that can be used as diagnostic markers for CRC.Conclusion:The present results conclude that Zn, Cu Se, and GPx can be used as diagnostic markers for CRC, where the decrease of these parameters may be associated with an increased risk of CRC and as indicators of the response to therapy.

282 Risk Factors for Colorectal Cancer in Patients Under 50: A Retrospective Study

INTRODUCTION: Colorectal cancer (CRC) incidence and mortality rates are rising in patients under age 50 for uncertain reasons. This study aims to identify risk factors and tumor characteristics of younger CRC patients aged 19–49 (Y-CRC), compared to a control group of CRC patients aged 50–60 (CRC-50+). METHODS: From a clinical and administrative database at a single institution, we identified patients with an initial CRC diagnosis between 2010–2012. Only histologically confirmed primary colon adenocarcinomas were included. Clinical and demographic characteristics were extracted via chart review. Bivariate and multivariable analyses were performed to compare Y-CRC and CRC-50+ groups. RESULTS: A total of 190 patients met our criteria (100 CRC = 50+, 90 Y-CRC). Most patients were white (123 patients, 64.7%), and 49 were black (25.8%). There were 90 female patients (47.4%). The average body mass index (BMI) was 27.1 kg/m2. 64 patients (33.7%) were current smokers. Family history of CRC or polyps was noted in 54 patients (18.4%). History of inflammatory bowel disease (IBD) was present in 11 patients (5.8%). The 12 patients (6.3%) with CRC-predisposing genetic syndromes were excluded from case-control analysis. We found no differences in BMI between groups (P = 0.8). There was a substantially higher proportion of Hispanic patients in Y-CRC group versus CRC-50+ group (13.9% vs. 0%, P &lt; 0.01). Diabetes was less common in Y-CRC than CRC-50+ (7.6% vs. 18.2%, P = 0.04). There was no statistically significant difference between groups in smoking history or family history of CRC/polyps. Although IBD was more common in Y-CRC (8.9% vs. 4.0%), the difference was not statistically significant (P = 0.2). Rectal cancers were slightly more common in Y-CRC (55.1% vs. 47.5%), but this was not statistically significant. Y-CRC patients were more likely to present at later stages and with synchronous lesions, compared to CRC-50+ cases. On multivariable analysis, Y-CRC was associated with Hispanic ethnicity and inversely associated with diabetes, after controlling for other factors (Table 2). CONCLUSION: Aside from a higher proportion of Hispanic ethnicity and lower proportion of diabetes among Y-CRC cases, the Y-CRC and CRC-50+ groups were comparable. We found no evidence of an association between family history, obesity or smoking with Y-CRC cases. Further work is needed to explore these and other potential risk factors for Y-CRC.

Biological Characteristics and Clinical Significance of ITGB1 and RHOC in Patients With Recurrent Colorectal Cancer

Colorectal cancer (CRC) is the leading cause of cancer mortality worldwide. Its poor prognosis can be ascribed primarily to high recurrence rates. Accordingly, the aim of this study was to identify novel prognostic biomarkers and therapeutic targets for management of CRC. To develop prognostic biomarkers, we performed RNA-seq analysis and real-time RT-PCR in primary cancer tissues with or without systemic recurrence. To characterize the molecular functions of the encoded proteins, CRC cells underexpressing or overexpressing the candidate genes were established and appropriate cell-based assays were applied. ITGB1 and RHOC mRNA levels were up-regulated in the recurrence group of CRC patients. Overexpression of ITGB1 or RHOC stimulated CRC cell proliferation, invasion and migration, whereas the opposite effects were observed in cells underexpressing either protein. Five-year recurrence-free survival rates were significantly higher in the ITGB1- and RHOC-underexpression groups than those in the overexpression. ITGB1 and RHOC are potential predictors of recurrence and therapeutic targets for CRC, possibly predicting a high-risk group of stage II patients.

Novel SFRP2 DNA Methylation Profile Following Neoadjuvant Therapy in Colorectal Cancer Patients with Different Grades of BMI.

The relationship between body weight and different cancers is now well-recognized and among such cancers, colorectal cancer (CRC) is reported most frequently. Our group recently published findings, through an epigenome-wide association study, suggesting that body mass index (BMI) could act as a relevant risk factor in the CRC. In addition, aberrant SFRP2 methylation is one of the major mechanisms for Wnt signaling activation in CRC. Conversely, neoadjuvant chemo-radiotherapy appears to alter the rectal cancer epigenome. This study was aimed to evaluate the effect of obesity, measured by BMI, on the methylation of SFRP2 in tumor samples of patients with CRC. Non-treated CRC patients and CRC patients treated with pre-operative neoadjuvant therapy from 2011 to 2013 were included and classified by BMI < 25.0 kg/m2 and BMI > 25.0 kg/m2. SFRP2 DNA methylation in tumor samples was measured by pyrosequencing. Our findings suggest a possible interaction between SFRP2 methylation levels and BMI in CRC tumor samples. The correlation of SFRP2 hypomethylation with an elevated BMI was stronger within the non-treated CRC patient group than within the treated CRC patient group. We have successfully demonstrated that the beneficial association of tumor SFRP2 hypomethylation is dependent on patient BMI in non-treated CRC, suggesting a possible tumor suppressor role for SFRP2 in overweight and obese patients. Additional studies of clinical pathologies would be necessary to strengthen these preliminary results.

Evaluation of Alpha 1-Antitrypsin for the Early Diagnosis of Colorectal Cancer.

Previous proteomic studies have identified alpha 1-antitrypsin (A1AT) as a potential serum biomarker for colorectal cancer (CRC). In this case-control study, we evaluated plasma A1AT concentration and activity as a biomarker for the early diagnosis of colorectal cancer in a group of 113 sporadic CRC patients. We also analyzed A1AT gene promoter methylation, and genotypes in this group of CRC patients. The plasma A1AT and CEA concentrations were measured using the nephelometric and ELISA methods, respectively. A1AT activity was determined by Trypsin Inhibitor Capacity assay. The genomic DNA from blood samples were subjected to Z and S genotype analysis using PCR-RFLP method and the gene promoter methylation in tumors and their adjacent normal tissues was determined by methylation specific-PCR assay. The plasma levels of A1AT and CEA in patients (median, 2.3g/L and 5.96ng/ml, respectively) were significantly higher than those in healthy controls (medians, 1.43g/L and 2.57ng/ml, respectively) (p = 0.0001). The plasma A1AT activity and concentrations were positively correlated with the tumor stage and well-discriminated between early and advanced stages. The A1AT activity in plasma was the most useful marker for CRC diagnosis (median 4.8mmol/min/ml in cases vs 1.91mmol/min/ml in controls, p = 0.0001). No deficient Z or S alleles of A1AT was observed in patients' genotype and the gene promoter tends to be more methylated in normal mucosa than in tumor tissues. We conclude that plasma A1AT activity has better sensitivity and specificity than CEA measurement for the early detection of CRC. Promoter demethylation might play a role in increasing plasma A1AT levels in CRC patients.

CCAT1 lncRNA Promotes Inflammatory Bowel Disease Malignancy by Destroying Intestinal Barrier via Downregulating miR-185-3p.

The long noncoding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) has been reported to play a vital role in the development of cancer. Although the link between inflammation and cancer initiation is well established, whether CCAT1 is involved in inflammation and promotes inflammatory bowel disease (IBD) malignancy remains undetermined. We aimed to investigate the expression of CCAT1 in IBD and the effect of CCAT1 overexpression on intestinal epithelial barrier function. The relationship between CCAT1 and the inflammation-related pathway was analyzed in both colorectal cancer (CRC) and IBD patients. Gene expression was detected by real-time polymerase chain reaction and Western blot. Transepithelial electrical resistance (TEER) and FD-4 flux measurement were used to test the effect of CCAT1 and miR-185-3p on intestinal epithelial barrier function. Luciferase assay was performed to validate the target site of miR-185-3p on 3'-UTR of MLCK mRNA. Gene set enrichment analysis revealed that several inflammation-related genes were enriched in the CCAT1 high-expressed group of CRC patients. The relationship between CCAT1 and inflammation activation in IBD patients was further confirmed. CCAT1 expression positively correlated with MLCK, which acts as a protein kinase to phosphorylate myosin light chain and induces tight junction protein distribution, whereas it was negatively correlated with miR-185-3p in IBD tissues. We also determined that CCAT1 overexpression increased Caco-2 monolayer permeability and upregulated MLCK. Furthermore, CCAT1-induced MLCK overexpression and IBD disease progression were significantly attenuated by miR-185-3p. The CCAT1/miR-185-3p/MLCK signaling pathway is strongly activated to destroy barrier function and promotes the pathogenesis of IBD.

Serum FBLN1 and STK31 as biomarkers of colorectal cancer and their ability to noninvasively differentiate colorectal cancer from benign polyps

PurposeThe aim of this work is to evaluate Fibulin-1 (FBLN1) and serine threonine kinase-31 (STK31) as colorectal cancer (CRC) tumour markers and their ability to differentiate it from colorectal benign lesions. Material and methodsIn this case-control study, FBLN1 and STK31 serum levels were measured in 120 participants; 49 CRC patients (group I), 26 patients with benign colorectal polyps (group II) and 45 healthy controls (group III). ResultsThe means of serum FBLN1 were 1.02 ± 0.95, 6.36 ± 2.55 and 6.26 ± 2.76 in group I, II and III respectively. Significant lower levels were found in group I compared to group II and III (both p < 0.001) with no significant difference between group II and III (p = .983).The means of serum STK31 were 13.51 ± 7.67, 5.98 ± 3.3 and 1.37 ± 1.22 in group I, II and III respectively with significant differences in-between the 3 groups (p < 0.001).Both FBLN1 and STK31 were superior to CEA as CRC screening biomarkers; with sensitivity 90.1% and 93% respectively and specificity 93.9% and 95.9% respectively.FBLN1 differentiated CRC from benign polyps with 91.8% sensitivity and 100% specificity. STK31 differentiated CRC from benign polyps with 93.9% sensitivity and 84.6% specificity. ConclusionFBLN1 and STK31 can be possible screening and differentiating biomarkers of CRC.

Circulating and Adipose Tissue mRNA Levels of Zinc-α2-Glycoprotein, Leptin, High-Molecular-Weight Adiponectin, and Tumor Necrosis Factor-Alpha in Colorectal Cancer Patients With or Without Obesity.

To explore zinc-α2-glycoprotein (ZAG), leptin, high-molecular-weight adiponectin (HMW-ADPN), and tumor necrosis factor-alpha (TNF-α) levels in serum and subcutaneous and visceral white adipose tissue (sWAT and vWAT) among normal weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). A total of 76 Chinese CRC patients (42 NW + CRC, 34 OW/OB + CRC) and 40 healthy controls were recruited. Serum levels of the adipokines of interest were measured by an enzyme-linked immunosorbent assay method, and their mRNA levels in sWAT and vWAT were determined by reverse transcription quantitative PCR methods. Serum ZAG levels in the NW + CRC group were significantly increased by 11.7% compared with the healthy controls. Serum leptin levels in the OW/OB + CRC group were found to be increased by 57.7%, while HMW-ADPN levels were decreased by 23.5% when compared with the NW + CRC group of CRC patients. Additionally, ZAG mRNA levels in sWAT were significantly reduced by 78.8% in OB + CRC in comparison with NW + CRC patients. ZAG mRNA levels were negatively associated with body mass index (BMI) in sWAT but positively correlated with BMI in vWAT. TNF-α mRNA levels in vWAT of OB + CRC patients were significantly increased by 2.8-fold when compared with NW + CRC patients. In particular, CRC was independently associated with serum ZAG levels. The risk of CRC in participants with high tertile serum ZAG levels was 5.84-fold higher than in those with low tertile ZAG levels after adjusting for age, gender, and other confounders [odds ratio (OR) = 6.84, 95% confidence interval (CI) 1.70-27.54, P = 0.03]. The CRC risk in participants with high tertile leptin levels was only 10.7% of those with low tertile leptin levels (OR = 0.11, 95% CI 0.01-0.89, P = 0.04). The area under the receiver operating characteristic (ROC) curve of ZAG was 0.66 (95% CI 0.54-0.77, P < 0.05). At the cutoff value of 1.42 µg/mL serum ZAG, the sensitivity and specificity for differentiating patients with CRC from controls were 62.2 and 69.2%, respectively. Serum ZAG levels were significantly increased in CRC patients. Subjects with higher circulating ZAG and lower leptin levels were more likely to have CRC than those with lower ZAG and higher leptin levels. Serum ZAG might be a potential diagnostic biomarker for CRC in the Chinese population.

THE RELATIONSHIP BETWEEN SERUM LEVEL OF MALONDIALDEHYDE AND PROGRESSION OF COLORECTAL CANCER.

SUMMARY – The purpose of the study was to assess the level of serum malondialdehyde (MDA) concentration and its association with the stage and histopathologic sizes of colorectal cancer (CRC). One hundred and two patients having undergone surgical treatment of CRC between January 2014 and December 2015 were included in this cross-sectional study. The patients were divided into four groups (stage I-IV) according to the TNM classification. Control group included 30 subjects with no signs of malignancy and inflammatory diseases. In each patient, preoperative blood samples were obtained for determination of MDA concentration by ELISA immunoassay. Serum levels of MDA were progressively increased in patients with CRC, reaching the highest value in the fourth stage of CRC. Serum concentrations of MDA were significantly higher in pT4 group as compared with pT3 and pT2 groups of CRC patients (p<0.01). Significantly higher levels of MDA were found in the N1 and N2 groups of CRC patients as compared with N0 group, as well as in patients with metastatic disease as compared with those without metastasis (p<0.001). In conclusion, the progression of CRC is associated with a significant increase in serum MDA levels.

Molecular and Clinicopathological Differences by Age at the Diagnosis of Colorectal Cancer.

We compared the clinicopathological and molecular profiles between different age groups of sporadic colorectal cancer (CRC) patients (age <50, 56–60, 60–70, 70–80, and >80); 1475 CRC patients were enrolled after excluding 30 individuals with Lynch syndrome. The mutation spectra for APC, TP53, KRAS, PIK3CA, FBXW7, BRAF, NRAS, HRAS, TGFbR, Akt1, and PTEN were analyzed using polymerase chain reaction (PCR), followed by MassArray and microsatellite (MSI-high) analysis by performing genotyping. Male patients (74.1%) were significantly predominant to females (25.9%) in the older age group (70–80, >80). There was an insignificantly linear trend between TNM staging and age-onset of CRC diagnosis. Patients aged < 50 had 58.7% diseases in the advanced stages (Stage III: 36.5% and IV: 22.2% respectively), while this decreased to 40.2% (Stage III: 26.2% and IV; 14.0% respectively) in patients >80. The distributions of mutation frequency were similar in majority of the genes studied among different age groups. Additionally, patients aged <50 had significantly higher frequency of MSI-high, PTEN, and HRAS mutations than those of other groups. Age-onset at diagnosis significantly affected overall survival (HR = 1.46; 95% CI: 1.35–1.58), but not cancer-specific survival (HR = 1.08; 95% CI: 0.99–1.18) in multivariate analysis. In conclusion, molecular and clinicopathological differences were not as significant among different age groups of CRC patients as previously suspected.

Impact of age and mismatch repair status on survival in colorectal cancer.

Previous studies have suggested that deficiencies in mismatch repair genes (dMMR) often occur in patients with colorectal cancer (CRC) and contribute to disease etiology. Here, we looked for a correlation of MMR status to disease outcomes from a large number of Chinese CRC patients stratified by the age of onset of disease. A total of 2233 CRC patients were analyzed and tissue biopsies of surgically removed tumors scored for MMR gene status. The patient distribution after classification consisted of 188 younger aged patients (20–39 years of age), 1024 middle aged patients (40–59 years of age), and 1020 older aged patients (60–85 years of age). In this analysis, the expression of four MMR genes was assessed by immunohistochemistry (IHC). We found that the young group of CRC patients with dMMR had higher overall survival (OS) than the young group of patients with proficient MMR (pMMR) (77% vs. 56%, P = 0.03). Middle‐aged patients with dMMR also had higher OS than middle‐aged group patients with pMMR (78% vs. 68%, P = 0.012). However, we found no statistical difference in OS between dMMR and pMMR status in the older group of patients (75% vs. 71%, P = 0.224). Finally, the middle‐ and older‐aged group set of patients had higher OS than the young group of patients (69% vs. 71% vs. 59%, P = 0.008). These data demonstrated that the age of disease onset can be an important factor to help evaluate the prognosis of CRC when combined with the analysis of MMR status within tumor biopsied tissue.