Colorectal Cancer Cancer Research Articles

Potential Mechanism of Immune Evasion Associated with the Master Regulator ASCL2 in Microsatellite Stability in Colorectal Cancer

Colorectal cancer (CRC) has two major subtypes, microsatellite instability (MSI) and microsatellite stability (MSS) based on the genomic instability. In this study, using computational programs, we identified 9 master transcription factors (TFs) based on epigenomic profiling in MSS CRC samples. Notably, unbiased gene set enrichment analysis (GSEA) showed that several master TFs were strongly associated with immune-related functions in TCGA MSS CRC tissues, such as interferon gamma (IFN-γ) and interferon alpha (IFN-α) responses. Focusing to the top candidate, ASCL2, we found that CD8+ T cell infiltration was low in ASCL2 overexpressed MSS CRC samples. Compared with other gastrointestinal (GI) cancers (gastric cancer, MSI CRC, and esophageal cancer), ASCL2 is specifically upregulated in MSS CRC. Moreover, we identified 28 candidate genes in IFN-γ and IFN-α response pathways which were negatively correlated with ASCL2. Together, these results link transcriptional dysregulation with the immune evasion in MSS CRC, which may advance the understanding of immune resistance and contribute to developing novel treatments of MSS CRC.

The Impact of Diabetes Mellitus on the Second Primary Malignancies in Colorectal Cancer Patients

IntroductionAll colorectal cancer (CRC) survivors have an increased risk of developing second primary malignancies (SPMs). The association between diabetes mellitus (DM) and the risk of cancer is well known. However, the role of DM and its therapy in the development of SPMs in CRC patients is not well described.MethodsIn this single-institutional retrospective analysis we identified 1,174 colorectal carcinoma patients, median follow-up 10.1 years, (median age 63 years, 724 men). All patients over 18 years with histologically confirmed CRC who were admitted in the period 1.1. 2003- 31.12.2013 and followed-up till 31.12. 2018 at the Masaryk Memorial Cancer Institute (MMCI) were screened for eligibility. The exclusion criteria were CRC diagnosed at autopsy, lost to follow-up and high risk of development of SPMs due to hereditary cancer syndrome. Tumours are considered multiple primary malignancies if arising in different sites and/or are of a different histology or morphology group. Comparisons of the basic characteristics between the patients with SPM and the patients without SPM were performed as well as comparison of the occurrence of SPMs by the site of diagnosis between the DM and non-DM cohorts and survival analyses.ResultsA SPM was diagnosed in 234 (20%) patients, DM in 183 (15%) patients. DM was diagnosed in 22.6% of those with SPM vs. in 13.8% of those without SPM (p=0.001). The most common types of SPMs in DM patients were other CRC, kidney, lung, bladder and nonmelanoma skin cancer, but only carcinoma of the liver and bile duct tracts was significantly more common than in the group without DM. Although breast cancer was the second most common in the group with DM, its incidence was lower than in the group without DM, as well as prostate cancer. A significantly higher incidence of SPMs was found in older CRC patients (≥ 65 years) and in those with lower stage colon cancer and DM. No significant difference in DM treatment between those with and without a SPM was observed including analysis of type of insulin.ConclusionCRC patients with diabetes mellitus, especially those with older age, and early stages of colon cancer, should be screened for second primary malignancies more often than the standard population. Patients without DM have longer survival. According to the occurrence of the most common second malignancies, a clinical examination, blood count, and ultrasound of the abdomen is appropriate, together with standard breast and colorectal cancer screening, and lung cancer screening under certain conditions, and should be recommended in CRC survivors especially in patients with intercurrent DM, however the necessary frequency of screening remains unclear.

Hedgehog Signaling in Colorectal Cancer: All in the Stroma?

Hedgehog (Hh) signaling regulates intestinal development and homeostasis. The role of Hh signaling in cancer has been studied for many years; however, its role in colorectal cancer (CRC) remains controversial. It has become increasingly clear that the “canonical” Hh pathway, in which ligand binding to the receptor PTCH1 initiates a signaling cascade that culminates in the activation of the GLI transcription factors, is mainly organized in a paracrine manner, both in the healthy colon and in CRC. Such canonical Hh signals largely act as tumor suppressors. In addition, stromal Hh signaling has complex immunomodulatory effects in the intestine with a potential impact on carcinogenesis. In contrast, non-canonical Hh activation may have tumor-promoting roles in a subset of CRC tumor cells. In this review, we attempt to summarize the current knowledge of the Hh pathway in CRC, with a focus on the tumor-suppressive role of canonical Hh signaling in the stroma. Despite discouraging results from clinical trials using Hh inhibitors in CRC and other solid cancers, we argue that a more granular understanding of Hh signaling might allow the exploitation of this key morphogenic pathway for cancer therapy in the future.

Phase I dose-escalation study of MCLA-158, a first-in-class bispecific antibody targeting EGFR and LGR5, in metastatic colorectal cancer (CRC).

62 Background: The WNT and EGFR signaling pathways are oncogenic and mitogenic drivers in CRC and other cancers. MCLA-158 is an ADCC enhanced human IgG1 cLC bispecific antibody identified from functional screening of CRC patient (pt)-derived organoids (PDO). MCLA-158 exposure leads to EGFR degradation in LGR5+ cancer and exhibits potent growth inhibition of RASmut and wt CRC PDOs, while minimal inhibition is observed in non-tumoral PDOs. Blockade of metastasis initiation was seen in preclinical in vivo models. MCLA-158 also demonstrated tumor regression or stasis in esophageal squamous (6/6) and gastric adenocarcinoma (6/8) PDX models selected for LGR5 and EGFR expression. Methods: Metastatic CRC pts progressing after oxaliplatin, irinotecan and fluoropyrimidines, and EGFR monoclonal antibodies if RASwt, received MCLA-158 IV every 2 weeks (q2w; 4-week cycle) in a phase I study. Safety, efficacy (per RECIST 1.1), PK and ADA were assessed. WNT and EGFR pathway components were evaluated in tumor tissue. EGFR pathway mutations (ctDNA) and soluble EGFR (sEGFR) were assessed in blood. PDOs were derived from baseline biopsies and assessed for MCLA-158 responsiveness. Results: As of 7 September 2020, 33 pts were treated over 11 dose levels (5 to 1500 mg, flat dose). At enrollment, median age was 58 years (range 35-76), ECOG PS 0/1:22/11, and 15 pts were RASmut. Pts had a median of 3 metastatic sites (range 1-12) with a median of 4 prior lines of therapy (range 1-10). A median of 2 MCLA-158 cycles (range 1-6) were administered. No dose limiting toxicity occurred. Infusion-related reactions were the most common AEs (67% of pts), occurred mostly in cycle 1 (21/22 pts), and were manageable. Other common related AEs included rash acneiform (36%), diarrhea (15%), pyrexia (9%) and asthenia/fatigue (9%). Related AEs were mostly mild or moderate; G3 related AEs were IRRs (4 pts; 12%), diarrhea and hypophosphatemia (1 pt each). The RP2D (1500 mg) was selected based on safety, PK and receptor occupancy prediction. MCLA-158 exhibited target-mediated clearance with proportional PK from 750 mg (t1/2 ~80 h at 1500 mg). Low ADA titers were seen in 3/23 pts, with no effect on PK. Target saturation is predicted at steady state serum trough levels. No clinical responses were observed during dose escalation. No/low baseline tumor EGFR expression (0-1+ IHC) was observed in 17/30 pts and non-elevated sEGFR levels ( < 4 ng/mL) in 18/22 pts. More than 1 activating mutation in EGFR signaling pathway genes were identified in ctDNA from 10/20 pts. 1/4 PDOs had > 30% growth inhibition with MCLA-158 ex vivo. MCLA-158 activity on PDOs correlated negatively with the presence of EGFR pathway resistance-mutations. Conclusions: Dual EGFR/LRG5 blockade with MCLA-158 was well tolerated, and the RP2D was 1500 mg IV q2w. Enrollment of pts with gastric and other non-CRC cancers at the RP2D continues in the expansion phase. Clinical trial information: NCT03526835.

Long intergenic non-coding RNA LINC00485 exerts tumor-suppressive activity by regulating miR-581/EDEM1 axis in colorectal cancer.

Long non-coding RNAs (lncRNA) play a vital role in colorectal cancer (CRC) progression. To investigate the role of long intergenic non-coding RNA LINC00485 in CRC, we performed in vitro functional experiments. LoVo tumor-bearing and liver metastasis mice were used as in vivo models. We found that LINC00485 expression was significantly lower in CRC tissues and cancer cells than in paired normal samples and human normal colonic epithelial cells. Lower expression of LINC00485 predicted poor prognosis in CRC patients. LINC00485 knockdown promoted the proliferation, migration, and invasion of FHC cells, while LINC00485 overexpression weakened these abilities of LoVo cells. MicroRNA miR-581 was the downstream target of LINC00485, which was downregulated in CRC samples and cancer cells compared to normal tissues and normal colonic epithelial cells. MiR-581 overexpression induced proliferation, migration, and invasion of FHC cells, while miR-581 antagomir treatment produced opposite results. MiR-581 directly targeted the 3'UTR of EDEM1 and inhibited its expression and induction of epithelial-mesenchymal transition of CRC. In mouse models, LINC00485 knockdown or down-regulation of miR-581 significantly repressed CRC cell growth and prevented CRC liver metastasis. Overall, LINC00485 suppressed CRC tumorigenesis and progression by targeting the miR-581/EDEM1 axis. LINC00485 may be a potential therapeutic target for CRC.

Health care resource utilization and treatment variability in the care of patients with advanced or metastatic colorectal or gastric cancer

Aims This study was designed to describe health care resource utilization (HCRU) of patients with metastatic colorectal cancer (CRC) or gastric cancer to test the hypothesis that greater treatment variability would be associated with increased HCRU. Methods A retrospective observational study using Marketscan claims data was conducted. Eligible patients had a first diagnosis of metastatic CRC or gastric cancer between 2004 and 2015 and must have received systemic anti-cancer therapy after diagnosis. Treatment variability was measured using the Herfindahl-Hirschman Index (HHI). HHI scores were stratified by quartile. HCRU variables were evaluated throughout the follow-up period and described by 6-month periods. Chi-square test was used for categorical variables and ANOVA for continuous variables. Results A total of 55,403 CRC and 9,073 gastric cancer patients were eligible. First-line HHI scores ranged from 0.1304–0.2778 for CRC and 0.0383–0.1778 for gastric cancer by state of residence. Statistically significant differences by HHI quartiles for HCRU in CRC included hospitalizations (p = 0.0003), ER visits (p < 0.0001), ER visits leading to hospitalization (p < 0.0001), and supportive care (all agents studied, p < 0.01). For gastric cancer, significant differences by HHI quartile were observed for ER visits (p = 0.002) and selected supportive care (G-CSF, erythropoiesis-stimulating agents, bisphosphonates, nutritional support, and antiemetics, each p < 0.05). No consistent increasing or decreasing trends were observed across the quartiles for either cohort. Limitations Large sample sizes could lead to statistical significance without being clinically meaningful. High treatment heterogeneity in the gastric cancer cohort and lack of a homogeneous quartile for comparisons limited the ability to evaluate HCRU by different levels of treatment variability. Conclusions Statistically significant relationships were observed between treatment variability as measured by HHI and increased HCRU, but no consistent directional trends in HCRU variables were observed. Therefore, this study failed to reject the null hypothesis of equivalent HCRU by level of treatment variability.

The role of CCR5 polymorphism in colorectal cancer and liver metastasis in the Tunisian population

Chemokines and their receptors are involved in cancer initiation and progression, including colorectal cancer (CRC) and liver metastasis formation. Our aim was to elucidate C-C chemokine receptor type 5 (CCR5) gene polymorphism (CCR5?32) impact on CRC and colorectal cancer liver metastases (CRLM) occurrence risk. We analyzed the CCR5 gene mutational status in 108 primary CRC cases, 35 CRLM and 248 healthy individuals, and evaluated CCR5 expression in healthy tissue and tumors. Rare allele ??32? was more frequent in controls (7.2% vs 2.8% in CRC). All 35 metastases had wild-type CCR5. Our analysis showed that CCR5 wild type has a significant risk of 2.73-fold (95% CI=1.22-7.31) to cause CRC while ?32 reduced the risks 0.36-fold (95% CI=0.13-0.82). For CRC, CCR5 correlated with left-sided tumors and liver metastases (P=0.040 and P= 0.039 respectively). As for CRLM, no correlation was found. Immunohistochemical profile analysis of CCR5 revealed a significant association with the male gender (P=0.049) and non-mucinous carcinomas (P&lt; 0.001) in primary CRC. CCR5 expression revealed an association with the degree of tumor differentiation for both CRC and CRLM (P &lt; 0.001). CCR5?32 might be a protective factor against CRC development and dissemination.

Immunotherapy in colorectal cancer.

The immune tumor microenvironment (TME) of colorectal cancer (CRC) is a crucial contributor to disease biology, making it an important target for therapeutic intervention. The diversity of immune cell populations within various subsets of CRC has led to the discovery that immune characterization of the TME has both prognostic and predictive value for patients. The convergence of improved molecular and cellular characterization of CRC along with the widespread use of immunotherapy in solid tumors has led to a revolution in the approach to clinical care. Monoclonal antibodies (mAbs) which target key immune checkpoints, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), have demonstrated remarkable clinical activity in microsatellite instability-high (MSI-H) CRCs and are now used in routine practice. The observation that MSI-H cancers are highly infiltrated with immune cells and carry a high neoantigen load led to the successful targeting of these cancers with immunotherapy. More recently, the Food and Drug Administration (FDA) approved a PD-1 inhibitor for microsatellite stable (MSS) cancers with high tumor mutation burden. However, the anti-tumor activity of immunotherapy is rare in the majority of CRC. While immune cell characterization does provide prognostic value in these patients, these observations have not yet led to therapeutic interventions. By delineating factors that predict efficacy, resistance, and therapeutic targets, ongoing research will inform the development of effective combination strategies for the vast majority of MSS CRC and immunotherapy-resistant MSI-H cancers.

Clinicopathological Significance of Tumor Stem Cell Markers ALDH1 and CD133 in Colorectal Carcinoma

Background & Objective:Colorectal cancer (CRC) is the third most common cancer worldwide with a high mortality rate. The main causes of death in patients are recurrence and metastasis which are mainly attributed to the small subpopulation of cells within tumors called cancer stem cells (CSCs). This study aimed to evaluate the correlation between the expression of ALDH1 and CD133 as CSC associated markers and clinicopathological characteristics in CRC.Methods:In this cross-sectional study, a total of 483 CRC tumor samples were immunohistochemically stained for detection of CD133 and ALDH1 markers. Correlations of marker expression with clinicopathological factors were also evaluated.Results:There was a significant correlation between the luminal intensity of CD133 and neural invasion (P=0.05) and between the cytoplasmic intensity of CD133 and metastasis (P=0.05). In terms of H-score, a positive significant relation was observed between cytoplasmic expression of CD133 and lymph node (P=0.02), neural (P=0.04) and vascular invasion (P=0.02). The ALDH1 cytoplasmic expression showed a significant correlation with tumor size (P=0.001).Conclusion:Our findings showed that increased expression of CD133 and ALDH1 is associated with tumor progression and worse outcomes in CRC patients. These markers can be good candidates for localized targeting of CSCs using antibodies. Future researches need to be improved approaches for early detection of CRC, and treatment monitoring for CRC and other cancers.

Metformin use and the Risk of Gastrointestinal Malignancies in Diabetic Populations: A Meta-Analysis.

Metformin use has been associated with a decreased risk of cancer and improvement in overall cancer survival rates. However, scant data available regarding metformin's role in the risk of Gastrointestinal (GI) malignancies in patients with type II diabetes. Our study aimed to conduct a meta-analysis to evaluate the association of metformin use and GI cancer risk. We conducted electronic search by two independent investigators using the PubMed and Cochrane library databases. Studies were assessed for design and quality, and a meta-analysis was conducted to quantify the effect of metformin on the odds of developing specific GI malignancies. The final papers that met our prespecified inclusion criteria included 4 case-control studies that address metformin's effect on pancreatic cancer, and 4 case-control studies that address metformin's effect on colorectal cancer in patients with type II DM. Of 2258 articles screened, 8 eligible studies were identified comprising 483,561 participants diagnosed with DM. Our analysis showed that metformin use was not associated with a significant effect on the odds of developing pancreatic cancer (OR .98; 95% CI 0.82-1.17, P=0. 83). Metformin use was associated with significantly lower odds of having Colorectal Cancer (CRC); (OR 0.84; 95% CI 0.81-0.87, p < 0.01). Sufficient data were not available to conduct analyses on the impact of metformin dose and duration. Our findings suggest that metformin could be a useful neoadjuvant agent for CRC cancer and as a possible preventive therapy for other inflammatory conditions related to colorectal pathologies such as adenomatous polyps and inflammatory bowel disease. Further research is warranted to elucidate the role of metformin on the risk of developing pancreatic cancer, given the complex nature of the organ's regulation on insulin production.

Predictive Value of Carcinoembryonic Antigen in Symptomatic Patients without Colorectal Cancer: A Post-Hoc Analysis within the COLONPREDICT Cohort.

We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3–3.1), CRC (HR 4.4, 95% CI 1.1–17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0–2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3–5.8), rectal bleeding (OR 0.3, 95% CI 0.1–0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7–7.1). However, CEA was increased only in 31.8% (95% CI, 16.4–52.7%) and 50% (95% CI, 25.4–74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRC.

P38γ Activation and BGP (Biliary Glycoprotein) Induction in Primates at Risk for Inflammatory Bowel Disease and Colorectal Cancer-A Comparative Study with Humans.

Colorectal cancer (CRC) is a common cause of cancer-related deaths largely due to CRC liver metastasis (CRLM). Identification of targetable mechanisms continues and includes investigations into the role of inflammatory pathways. Of interest, MAPK is aberrantly expressed in CRC patients, yet the activation status is not defined. The present study assessed p38γ activation in CRC patients, cancer cells, and tissues of cotton top tamarin (CTT) and common marmoset (CM). The primate world is an overlooked resource as colitis-CRC-prone CTT are usually inure to liver metastasis while CM develop colitis but not CRC. The results demonstrate that p38γ protein and phosphorylation levels are significantly increased in CRC patients compared to normal subjects and CTT. Furthermore, p38γ phosphorylation is significantly elevated in human CRC cells and hepatoblastoma cells but not in CM colon. Additionally, carcinoembryonic antigen (CEA) and biliary glycoprotein (BGP) are induced in the CRC patients that showed p38γ phosphorylation. Inhibition of p38 MAPK in CRC cells showed a significant decline in cell growth with no effect on apoptosis or BGP level. Overall, p38γ is activated in CRC tumorigenesis and likely involves CEA antigens during CRLM in humans but not in the CTT or CM, that rarely develop CRLM.

Intratumor Heterogeneity of HLA-G Expression in Cancer Lesions.

Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.

Screeners vs. Non-screeners for Colorectal Cancer among People over 50 Years of Age: Factual and Psychological Discriminants.

Colorectal cancer (CRC) is the third most frequent form of cancer worldwide, and approximately one third of cases have a positive family history of CRC or associated cancers. Colonoscopy is one of the most effective methods of screening for CRC. Uptake of colonoscopy is suboptimal, and many countries lack a national screening programme. Our study aims at exploring and ranking several factual and psychological variables according to their accuracy in discriminating between screeners and non-screeners for CRC in a convenience sample of people over 50 years of age. The study included 103 individuals aged over 50 years, recruited from day centres for the elderly. We explored socio-demographic variables, frequency of colonoscopy, previous recommendations for screening, health literacy and family history of cancer. Receiver operating characteristic (ROC) analysis was used to establish the discriminative value for each variable between the positive and negative decision for colonoscopy screening. Areas under the curve (AUC) and their equivalent Cohen's d values were calculated. Almost a quarter (25.75%) of participants reported previous colonoscopy screening. ROC curve analysis shows that colonoscopy uptake is best discriminated by perceived benefits of screening (AUC=0.71, d=0.78, p<0.001), previous recommendations for screening (AUC=0.68, d=0.69, p<0.001) and previous recommendations for preventive measures (AUC=0.67, d=0.64, p<0.001). Recommendations from healthcare professionals lead to improved colonoscopy uptake when emphasising the benefits of screening. Results can further inform psychosocial interventions by bringing empirical evidence to emphasize screening benefits and explicit recommendations for individuals at risk for CRC cancer.

Curcumin: A therapeutic strategy for colorectal cancer?

Colorectal cancer (CRC) is the second cause of cancer death worldwide. The metastatic disease is mainly treated with aggressive therapies consisting on combinations of cytotoxic chemotherapy plus anti-EGFR or anti-VEGF drugs. In spite of the improvements in clinical outcomes achieved in the last decade, these are the result of multiple new combinations using the existing therapeutic options and the introduction of regorafenib and TAS-102 in second or later lines of treatment. As immunotherapies are limited to less than 5% of CRC patients harboring tumors with deficient mismatch repair, there is an urgent need of finding new drugs to increase our patients' survival opportunities. Among all the natural products that are candidates to be used for the treatment of CRC cancer, curcumin (the golden spice) is in the spotlight. Used for centuries in the Ayurveda medicine, its demonstrated anticancer properties and low toxicity profile made it the focus of hundreds of preclinical and clinical investigations. So far we know that it can be combined with most of the aforementioned drugs in a safe and synergistic way. Regretfully, its poor bioavailability has been one of the main issues for its successful introduction in the clinic. Nevertheless, a plethora of new formulations with a huge increase in bioavailability are under study with promising results. In this review we discuss the possibility of incorporating curcumin in the treatment of CRC; specifically, we review preclinical and clinical data supporting its possible combination with current therapies as well as new formulations under clinical study. It is time for the golden spice revolution.

Prognostic implications of metabolism-associated gene signatures in colorectal cancer.

Colorectal cancer (CRC) is one of the most common and deadly malignancies. Novel biomarkers for the diagnosis and prognosis of this disease must be identified. Besides, metabolism plays an essential role in the occurrence and development of CRC. This article aims to identify some critical prognosis-related metabolic genes (PRMGs) and construct a prognosis model of CRC patients for clinical use. We obtained the expression profiles of CRC from The Cancer Genome Atlas database (TCGA), then identified differentially expressed PRMGs by R and Perl software. Hub genes were filtered out by univariate Cox analysis and least absolute shrinkage and selection operator Cox analysis. We used functional enrichment analysis methods, such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, to identify involved signaling pathways of PRMGs. The nomogram predicted overall survival (OS). Calibration traces were used to evaluate the consistency between the actual and the predicted survival rate. Finally, a prognostic model was constructed based on six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK1, and ADCY5), and the risk score was an independent prognostic prognosticator. Genetic expression and risk score were significantly correlated with clinicopathologic characteristics of CRC. A nomogram based on the clinicopathological feature of CRC and risk score accurately predicted the OS of individual CRC cancer patients. We also validated the results in the independent colorectal cancer cohorts GSE39582 and GSE87211. Our study demonstrates that the risk score is an independent prognostic biomarker and is closely correlated with the malignant clinicopathological characteristics of CRC patients. We also determined some metabolic genes associated with the survival and clinical stage of CRC as potential biomarkers for CRC diagnosis and treatment.

Whole grain and dietary fiber intake and risk of colorectal cancer in the NIH-AARP Diet and Health Study cohort

Whole grains and other foods containing fiber are thought to be inversely related to colorectal cancer (CRC). However, whether these associations reflect fiber or fiber source remains unclear. We evaluated associations of whole grain and dietary fiber intake with CRC risk in the large NIH-AARP Diet and Health Study. We used Cox proportional hazard models to estimate HRs and 95% CIs for whole grain and dietary fiber intake and risk of CRC among 478,994 US adults, aged 50-71 y. Diet was assessed using a self-administered FFQ at baseline in 1995-1996, and 10,200 incident CRC cases occurred over 16 y and 6,464,527 person-years of follow-up. We used 24-h dietary recall data, collected on a subset of participants, to evaluate the impact of measurement error on risk estimates. After multivariable adjustment for potential confounders, including folate, we observed an inverse association for intake of whole grains (HRQ5 vs.Q1 : 0.84; 95% CI: 0.79, 0.90; P-trend<0.001), but not dietary fiber (HRQ5 vs. Q1: 0.96; 95% CI: 0.88, 1.04; P-trend=0.40), with CRC incidence. Intake of whole grains was inversely associated with all CRC cancer subsites, particularly rectal cancer (HRQ5 vs. Q1: 0.76; 95% CI: 0.67, 0.87; P-trend<0.001). Fiber from grains, but not other sources, was associated with lower incidence of CRC (HRQ5 vs. Q1: 0.89; 95% CI: 0.83, 0.96; P-trend<0.001), particularly distal colon (HRQ5 vs. Q1: 0.84; 95% CI: 0.73, 0.96; P-trend=0.005) and rectal cancer (HRQ5 vs. Q1: 0.77; 95% CI: 0.66, 0.88; P-trend<0.001). Dietary guidance for CRC prevention should focus on intake of whole grains as a source of fiber.

Somatic mutations in colorectal cancer are associated with the epigenetic modifications.

Colorectal cancer (CRC) mostly arises from progressive accumulation of somatic mutations within cells. Most commonly mutated genes like TP53, APC and KRAS can promote survival and proliferation of cancer cells. Although the molecular alterations and landscape of some specific mutations in CRC are well known, the presence of a somatic mutation signature related to genomic regions and epigenetic markers remain unclear. To find the signatures from a random distribution of somatic mutations in CRCs, we carried out enrichment analysis in different genomic regions and identified peaks of epigenetic markers. We validated that the mutation frequency in miRNA is dramatically higher than in flanking genomic regions. Moreover, we observed that somatic mutations in CRC and colon cancer cell lines are significantly enriched in CTCF binding sites. We also found these mutations are enriched for H3K27me3 in both normal sigmoid colon and colon cancer cell lines. Taken together, our findings suggest that there are some common somatic mutations signatures which provide new directions to study CRC.

TRIM21 Is Decreased in Colitis-associated Cancer and Negatively Regulates Epithelial Carcinogenesis.

Tripartite motif-containing (TRIM)21 is reported to be associated with the regulation of immune response in gut mucosa. Here we studied the underlying mechanisms of TRIM21 in the pathogenesis of colitis-associated cancer (CAC). We analyzed TRIM21 expression in tumor tissues from patients with colorectal cancer (CRC) and ulcerative colitis (UC)-associated cancer by immunohistochemistry and real-time polymerase chain reaction and established a CAC model in TRIM21-∕- and wild type mice by azoxymethane (AOM) and dextran sodium sulfate (DSS). Associated gene expression of tumor cell proliferation, adhesion, tissue remodeling and angiogenesis, and inflammatory cytokines were examined in normal colon and CAC by immunohistochemistry and real-time polymerase chain reaction. Expression of TRIM21 was found to be decreased in tumor tissues from patients with CRC and UC-associated cancer than that in controls, and TRIM21-∕- deficiency promoted AOM/DSS-induced CAC, characterized by more weight loss and multiple, large colon tumors in TRIM21-∕- mice. Moreover, associated gene expression of tumor cell proliferation (eg, Ki67), tissue remodeling and angiogenesis (eg, MMP10, HIF1-α, COX2, Ang4), and pro-inflammatory cytokines (eg, IL-6, TNF-α, IL-1β) markedly upregulated, whereas associated gene expression of tumor cell adhesion (E-cadherin) and inflammatory cytokines (eg, IL-10, TGF-β, Foxp3, IFN-γ) downregulated in tumor tissues from TRIM21-/- mice compared with controls. TRIM21 is decreased in colitis-associated cancer and negatively regulates intestinal epithelial carcinogenesis by modulating epithelial cell proliferation, adhesion, tissue remodeling and angiogenesis, and pro-inflammatory responses. Therefore, TRIM21 may serve as a novel therapeutic target for CAC therapy.

Comparison of Molecular, Clinicopathological, and Pedigree Differences Between Lynch-Like and Lynch Syndromes.

In this study, we compared the molecular, clinical, and pathological characteristics, as well as pedigrees, between patients with Lynch-like syndrome (LLS) and confirmed Lynch syndrome (LS) to develop appropriate management strategies for patients with LLS and their affected family members. Between June 2008 and September 2018, 81 patients with LLS and 47 patients with LS who developed colorectal cancer (CRC) were enrolled in this study. Multigene panel testing included 139 genes and was performed for all patients. The variants identified in each group were described, and clinicopathological characteristics and pedigrees were compared between the two groups. In the LLS group, a total of 52 variants were detected in 44 (54.3%) patients. Among the 52 variants, 17 were variants of unknown significance in mismatch repair genes, and the other most frequently mutated genes were MUYTH, POLE, BRCA2, and GJB2. The proportion of early-onset patients was significantly higher among the LS probands than among the LLS probands (74.5 and 53.1%, respectively; χ2 = 5.712, P = 0.017). On the other hand, the proportion of primary CRC developed in the rectum was higher in the LLS group than in the LS group (25.9 and 10.6%, respectively; χ2 = 2.358, P = 0.046). There were no significant differences in the occurrence of metachronous CRC (P = 0.632) and extra-colorectal cancer (extra-CRC) (P = 0.145) between the two groups. However, analysis of pedigrees showed that more patients developed CRC in the LS families (P = 0.013), whereas more patients with extra-CRC were observed in the LLS families (P = 0.045). A higher prevalence of male patients was observed in the LLS families (P = 0.036). In conclusion, LLS should be classified as a mixed entity, containing cases of LS, other hereditary cancer syndromes, and sporadic CRC. The high risks of CRC and extra-CRCs, which were found in this study, suggest tailored management policy and surveillance should be formulated based on individual and family risk. The surveillance regimen can be based on the presence of confirmed pathogenic/likely pathogenic germline variant(s) and family history.