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PubMedDate not supplied

Overexpression of c-erbB-2 mRNA and/or c-neu oncoprotein is a predictor for metastases from colorectal cancer.

Studies in epithelial cancer, including colorectal cancer, suggest that c-erbB-2 may be an important gene in metastatic disease. The expression of c-erbB-2 mRNA and c-neu were assessed in 25 human non-metastasising colorectal cancers and 34 primary metastasising colorectal cancer and their liver metastasis by in situ hybridisation and immunohistochemistry respectively. The metastasising colorectal cancers and their liver metastases expressed c-erbB-2 mRNA (76%, 70%) and c-neu (70%, 68%) at significantly higher levels than the nonmetastasising tumours (28% and 36% respectively chi-squared: p < 0.003 and p < 0.04). Moreover, c-erbB-2 mRNA predicted the development of liver metastases in tumours that had not metastasised to lymph nodes (p = 0.002). This gene may play an important role in the development of metastasis in colorectal cancer and its mRNA expression may have important implications for deciding which patients with lymph node negative disease require chemotherapy.

Colorectal Neoplasms↗

PubMed1998

Reciprocal relationship between the tumor suppressors p53 and BAX in primary colorectal cancers.

Though most colorectal cancers show allelic losses, a subset of colorectal cancers (microsatellite instability or MSI-positive cancers) develop numerous small insertion and deletion mutations in repetitive DNA. Some of these sequences occur in coding regions of cancer related genes which, when targeted by frameshift mutations, produce truncations in their protein product. Such a gene is the proapoptotic tumor suppressor, BAX, mutated by frameshifts within a polyG sequence in approximately 50% of MSI-positive colorectal cancers. BAX is directly transactivated by p53, a gene commonly mutated in colorectal cancers but not often in MSI-positive lesions. Here we sought to characterize the relationship between BAX and p53 by simultaneously analysing a selected series of 65 colorectal tumors for mutations in the entire coding regions of both genes. The tumors comprised 19 MSI-high, 12 MSI-low and 34 MSI-null cancers. Eight of 19 MSI-high sporadic colorectal cancers (42%) contained insertions and deletions at the polyG tract in the BAX gene. In addition, three somatic BAX missense mutations were identified in two tumors. A single missense mutation was detected in an MSI-high tumor that also contained a frameshift microdeletion, and two missense mutations were identified in an MSI-null tumor wild-type for p53. p53 mutations were detected in 5/12 MSI-low tumors (42%) and 12/34 MSI-null tumors (35%). Of significance, no p53 mutations were detected in MSI-high tumors. This study demonstrates that a reciprocal relationship exists between p53 and BAX in sporadic colorectal cancers, and further supports the hypothesis that MSI-low tumors are biologically similar to MSI-null tumors.

Amino Acid Sequence↗

PubMed2003

Cancer physicians' attitudes toward colorectal cancer follow-up.

BACKGROUND: The optimal follow-up strategy for colorectal cancer is unknown. MATERIALS AND METHODS: We surveyed all Canadian radiation oncologists, medical oncologists and surgeons specializing in colorectal cancer to assess their recommendations for follow-up after potentially curative treatment, the beliefs and attitudes underlying these practices, and the cost implications of different follow-up strategies. RESULTS: One hundred and sixty practitioners (58%) returned completed surveys. Most recommended clinical assessments every 3-4 months in the first 2 years including carcino-embryonic antigen testing, gradually decreasing in frequency over 5 years. Ninety per cent recommend a surveillance colonoscopy in the first year. The majority felt that specialist involvement in follow-up was important because of the increased opportunities for patients to contribute to research (76%) and teaching (73%). About half felt that specialists were more efficient at providing follow-up than primary care physicians, but these same physicians recommended significantly longer and more expensive follow-up routines on average than others. Primary care physicians were felt to be important allies, especially in managing the psychosocial concerns of patients. CONCLUSIONS: Surveillance practices are generally in keeping with published recommendations. Most specialists feel that they should remain involved in follow-up, but this may result in increased resource utilization.

Adult↗

PubMed2005

A new single nucleotide polymorphism in the insulin-like growth factor I regulatory region associates with colorectal cancer risk in singapore chinese.

Elevated levels of plasma insulin-like growth factor I (IGF-I) are a potential risk factor for several cancers, including colorectal cancer. Physiologic levels of plasma IGF-I vary greatly; this variation may be in part genetically determined. We identified two single nucleotide polymorphisms (SNP) in perfect linkage disequilibrium with each other and in partial linkage disequilibrium with a previously studied cytosine-adenine microsatellite [-969(CA)(n)]. We investigated one of the SNPs, -533T/C,and the 969(CA)(n) in relation to the risk of colorectal cancer in a case-control study nested within a cohort of Singapore Chinese (cases/controls = 290:873). The (CA)(21) allele, rather than the previously implicated (CA)(19) allele, was associated with a reduced risk of colorectal cancer (odds ratio for 21/21 versus all other genotypes, 0.48; 95% confidence interval, 0.28-0.84). For the -533C/T SNP, persons carrying one or more copies of the C allele had a decreased in risk of colorectal cancer compared with noncarriers (odds ratio for CC/CT versus TT, 0.58; 95% confidence interval, 0.41-0.82). This association was specific for colon, as opposed to rectal cancer and was modified by age. We also examined a functional insulin-like growth factor binding protein (IGFBP3) promoter SNP, -202 A/C, previously reported to predict serum IGFBP3 levels. Although we were able to confirm this genotype-phenotype association, the -202A/C IGFBP3 SNP was not significantly associated with colorectal cancer risk. In conclusion, we report a novel SNP in the IGF-I regulatory region that is associated with colorectal cancer risk.

Alleles↗

PubMed2026

Integrated single-cell and spatial transcriptomic analyses reveal malignant epithelial glycolytic heterogeneity and spatial niche remodeling during colorectal cancer progression.

Colorectal cancer (CRC) progression is shaped by metabolic reprogramming and complex interactions within the tumor microenvironment. However, the cellular heterogeneity, spatial organization, and clinical relevance of glycolytic activity in CRC remain incompletely understood. In this study, we integrated single-cell RNA sequencing, bulk transcriptomics, and spatial transcriptomics data to systematically characterize glycolytic heterogeneity in CRC. Glycolytic activity was quantified using five independent scoring methods, consistently showing that epithelial cells exhibited the highest glycolytic activity across the two single-cell cohorts. Stratification of CopyKAT-verified aneuploid malignant epithelial cells into high-glycolysis (HG) and low-glycolysis (LG) subgroups by glycolysis scores revealed that HG cells exhibited higher stemness scores and chromosomal copy number variations. Cell-cell communication analysis revealed that, compared with LG cells, HG cells exhibited increased interaction frequency and strength with immune and stromal populations, indicating enhanced malignant epithelial-microenvironment crosstalk. Spatial transcriptomics analyses further revealed that glycolytic activity varied across normal colorectal tissue, primary CRC, and colorectal liver metastases, accompanied by progressive remodeling of epithelial-associated spatial niches and MIF-mediated intercellular communication. Bulk transcriptomic analysis identified a glycolysis-related prognostic signature with robust predictive performance, which served as an independent prognostic factor for overall survival in CRC cohorts. Collectively, these findings indicate that glycolytic heterogeneity is a key feature of CRC malignant epithelial cells and is closely associated with tumor progression, microenvironmental remodeling, and clinical outcomes.

Humans↗

PubMed2005

Gynecologic cancer as a "sentinel cancer" for women with hereditary nonpolyposis colorectal cancer syndrome.

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40-60% lifetime risk for colon cancer, a 40-60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their "sentinel cancer." METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the "sentinel cancer," preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome.

Adult↗

PubMed2026

Multi-omics Investigations of Immune Microenvironment of Human Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although immunotherapy has improved outcomes for a subset of patients, its limited efficacy in many cases highlights the need for a more comprehensive understanding of the CRC immune microenvironment. This study aimed to characterize the molecular landscape of the CRC immune microenvironment using an integrated multi-omics approach and to identify candidate regulatory molecules associated with immune remodelling. MATERIALS AND METHODS: We integrated structural variation, DNA methylation, chromatin accessibility, proteomic, and phosphoproteomic data generated from an in-house CRC cohort with transcriptomic data from The Cancer Genome Atlas (TCGA). Analyses focused on 1,539 immune-related genes (IRGs) associated with CD4+ T cells, B cells, and natural killer (NK) cells. Multi-layered genomic and proteomic analyses were performed to identify altered immune-related pathways, hub genes, candidate transcription factors, and upstream kinases. RESULTS: Higher infiltration of CD4+ T cells, B cells, and NK cells was associated with CRC. IRGs exhibited widespread alterations across genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic levels. IL10, LEP, ITGAM, and EGFR emerged as candidate hub genes. EGFR phosphorylation at S991 and T693 was significantly decreased in CRC. STAT2 and HSF1 were identified as candidate upstream transcription factors, while CDK2 emerged as a candidate upstream kinase associated with immune infiltration and immune checkpoint expression. CONCLUSION: This study provides a systematic multi-omics characterization of immune microenvironment remodelling in CRC and identifies candidate molecular regulators that may serve as potential targets for future immunotherapy research.

Humans↗

PubMed2026

The bioinformatics approach to identifying pathogenic variants for colorectal cancer (CRC).

Colorectal cancer (CRC) is the third most prevalent cancer globally, accounting for 9.6% of newly diagnosed cases and 9.3% of cancer-related deaths. It develops from the uncontrolled proliferation of glandular cells in the colon and rectum and is categorized into three primary types: sporadic, hereditary, and colitis-associated. While genetic susceptibility is a key factor in CRC pathogenesis, identifying high-impact pathogenic variants remains a significant challenge. This study integrates bioinformatics and population genetics approaches to identify CRC-associated single-nucleotide polymorphisms (SNPs) with potential clinical significance. CRC-associated SNPs were extracted from the Genome-Wide Association Studies (GWAS) Catalog, functionally annotated via HaploReg, and validated via Ensembl. In addition, expression quantitative trait locus (eQTL) data from the GTEx database were used to assess the effects of these variants on gene expression across human tissues. Our analysis identified three high-priority SNPs (rs9379084, rs3184504, and rs11557154) associated with the RREB1, ATXN2, SH2B3, and DCAF12 genes, which exhibited marked allele frequency differences among populations. These findings suggest potential biomarkers for CRC risk assessment and highlight the importance of genetic screening across diverse populations.

Bioinformatics↗

PubMed2026

A machine learning-derived and functionally validated circadian rhythm signature predicts clinical outcomes and in silico drug sensitivity in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) displays considerable heterogeneity in clinical outcomes, highlighting the need for reliable prognostic biomarkers. While the aberrant expression of circadian rhythm-related genes has been implicated in cancer pathogenesis, its comprehensive role in CRC progression and predicted therapeutic vulnerabilities remains inadequately characterized. METHODS: Bulk and single-cell RNA-sequencing data were integrated from multiple CRC cohorts. A circadian rhythm signature (CRS) was developed through machine learning algorithms and validated for prognostic value. Comprehensive analyses of tumor microenvironment, genomic alterations, and drug sensitivity were performed. Furthermore, the biological function of the core gene, BHLHE40, was validated in CRC cell lines through CCK-8, EdU, and wound healing assays. RESULTS: Single-cell analysis demonstrated an elevated expression signature of circadian rhythm-related genes in dendritic cells. The optimized CRS, comprising 14 circadian rhythm-related genes, successfully categorized patients into high- and low-risk groups. Patients with a high CRS showed markedly poorer overall survival and computationally inferred immunosuppressive features, including reduced CD8+ T cell infiltration and increased M2 macrophage polarization. Genomic analysis revealed enhanced mutation burden in TP53 and alterations in RTK-RAS/WNT pathways. Notably, in vitro assays confirmed that BHLHE40 is significantly overexpressed in CRC cells. Knockdown of BHLHE40 markedly inhibited tumor cell proliferation and migration. Drug sensitivity profiling identified bexarotene and SMER-3 as potential therapeutic options for high-CRS patients. A nomogram integrating CRS with clinical parameters demonstrated superior predictive accuracy for 1-, 3-, and 5-year survival. CONCLUSIONS: The CRS represents a promising prognostic biomarker that reflects tumor immune status and genomic features, providing valuable insights for personalized treatment strategies in CRC.

Circadian rhythm↗

PubMed2026

A novel lactylation-related gene signature deciphers the immunosuppressive microenvironment and stratifies precision therapy in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer mortality, largely due to the heterogeneity of the tumor microenvironment (TME) and the limited efficacy of immunotherapy in microsatellite stable (MSS) tumors. Histone lactylation, a post-translational modification derived from the Warburg effect, serves as a critical bridge linking metabolic reprogramming to gene regulation and immune evasion; however, its specific prognostic value and clinical implications in CRC remain to be fully elucidated. METHODS: In this study, we systematically analyzed transcriptome profiling data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts, supplemented by single-cell RNA sequencing (scRNA-seq) analysis and Human Protein Atlas (HPA) protein-level validation. By integrating univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) analysis, and multivariate Cox regression, we constructed a novel lactylation-related gene (LRG) risk signature. We extensively evaluated the association between this risk signature and patient prognosis, immune infiltration patterns, somatic mutations, and therapeutic sensitivity. RESULTS: A robust 9-gene prognostic signature (DHRS7, SPR, MBD2, RBM17, CSRP2, S100A4, TMSB4X, TKT, COPS4) was identified and corroborated at the protein level. Patients with high risk scores exhibited significantly worse overall survival (OS) across the training and two independent validation cohorts. Immunogenomic and scRNA-seq analyses revealed that high-risk tumors were characterized by an immunosuppressive and stromal-dense microenvironment-with stromal cells exhibiting the highest lactylation risk scores-enriched with regulatory T cells (Tregs), and frequently harbored PIK3CA mutations. Differential expression analysis indicated that this immune exclusion is structurally maintained by enriched extracellular matrix (ECM) organization and TGF-β signaling. Conversely, low-risk tumors displayed an inflamed phenotype with active antitumor immunity. Pharmacogenomic prediction identified distinct therapeutic stratifications: low-risk patients exhibited significant sensitivity to standard chemotherapeutics (fluorouracil, oxaliplatin) and EGFR/HER2 inhibitors (e.g., lapatinib, erlotinib). In contrast, high-risk patients showed specific vulnerabilities to novel targeted agents, including PI3K pathway inhibitors (TG-100-115, XL765), microenvironment-modulating agents (sildenafil, GANT-61), and epigenetic inhibitors (UNC0638). CONCLUSION: We established a novel lactylation-related risk signature that effectively stratifies CRC patients by prognosis and TME characteristics. By elucidating the crosstalk between metabolic dysregulation, stromal barriers, and immune exclusion, this study provides potential biomarkers and stratified therapeutic strategies-ranging from standard chemotherapy to targeted metabolic and stromal interventions-to optimize precision medicine for CRC patients.

Colorectal cancer↗

PubMed2026

Multi-omics characterization of a GPRC5A+ epithelial subpopulation associated with malignant features in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) exhibits marked cellular heterogeneity, and the cellular context of malignancy-associated epithelial programs remains incompletely defined. METHODS: We integrated 2,993 CRC samples spanning bulk RNA-seq (n = 2,568; two OS/RFS cohorts), scRNA-seq (281,961 cells/152 specimens), spatial transcriptomics (n = 6), and proteomics (n = 267). Analyses included single-cell integration/annotation, GSVA/HALLMARK, interactome, pseudotime, and ligand-receptor mapping; functional CRISPR assays, EMT immunoblotting, and xenografts; TF profiling (SCENIC/JASPAR/ChIP-qPCR); and exploratory drug-response prediction (OncoPredict), cell-sensitivity assays, and docking/MD modeling. RESULTS: We constructed a stage-stratified single-cell atlas and resolved eleven malignant epithelial subsets, characterizing Epi_4 as late-stage-enriched with EMT, hypoxia, and inflammatory programs and adverse OS/RFS. GPRC5A marked this subset, which we define as GPRC5A+Epi; its expression rose from stage I→IV and was associated with poor outcomes across cohorts, with concordant spatial/proteomic observations. GPRC5A perturbation affected CRC proliferation, migration/invasion, EMT, and xenograft tumorigenicity, supporting a functionally important role in the tested models. SCENIC and ChIP-qPCR supported FOSL1 as an upstream regulator that occupies the GPRC5A promoter. Spatial and ligand-receptor analyses predicted close association and potentially reciprocal signaling between GPRC5A+Epi and POSTN+fibroblasts (COL1A1-SDC4, COL1A1/1A2-ITGA2/ITGB1, PPIA-BSG); concurrent high GPRC5A+Epi/POSTN+Fib signatures were associated with inferior OS/RFS. Drug-response analyses identified an association between GPRC5A status and trametinib sensitivity. Docking/MD produced a computational model of a possible trametinib-GPRC5A interaction, which remains experimentally unvalidated. CONCLUSIONS: GPRC5A⁺Epi is a malignancy-associated epithelial state in CRC, and GPRC5A is functionally important for malignant phenotypes in the tested models. Its inferred relationships with POSTN⁺ fibroblasts and the trametinib findings should be regarded as hypothesis-generating pending functional crosstalk, direct-binding, and therapeutic validation.

Humans↗

PubMed2026

Identification and evaluation of glutamine-related gene characteristics based on multi-omics to predict the prognosis of patients with colorectal cancer.

BACKGROUND: Colorectal cancer (CRC), a prevalent malignancy of the gastrointestinal tract, ranks among the leading causes of cancer-related morbidity and mortality. Its clinical course is marked by high fatality and poor prognosis. Elucidating the mechanisms underlying CRC initiation and recurrence is therefore critical for identifying novel therapeutic targets. METHODS: This study incorporated two datasets, TCGA-CRC and GSE17537. A total of 84 glutamine metabolism-related genes (GMRGs) were identified, and differential expression analysis was conducted using the TCGA-CRC dataset. Weighted Gene Co-expression Network Analysis (WGCNA) was applied to determine gene modules most strongly associated with GMRG scores. Single-cell RNA sequencing (scRNA-seq) was utilized to characterize key cellular clusters and to identify differentially expressed genes (DEGs) between high and low glutamine metabolism (GM) groups. Overlapping GMRGs were visualized using the ggVennDiagram package in R. A CRC risk prediction model was developed through Cox proportional hazards and LASSO regression analyses, with performance evaluated by ROC curves. Cell type enrichment across 64 immune and stromal populations was assessed via xCell, and intergroup differences were tested using the Wilcoxon rank-sum test. TIDE scores were used to estimate immunotherapy responsiveness, while oncoPredict facilitated drug sensitivity profiling. PCOLCE2 expression in CRC was validated by RT-qPCR and Western blotting. Its functional role was examined through CCK-8 assays, invasion and migration tests, flow cytometry, and glutamate quantification. RESULTS: ScRNA-seq analysis identified two key cell populations and 437 DEGs associated with GM status. WGCNA pinpointed the MEgreen module as most significantly correlated with GMRG scores, encompassing 1075 genes. Integration of DEGs, module genes, and GM-related DEGs yielded 60 candidate genes for downstream analysis. A GMRG-based prognostic model comprising six genes (SRPX, CXCL1, GPX3, PCOLCE2, CLU, SEMA3E) demonstrated strong predictive performance. Prognostic gene expression correlated with immune and stromal infiltration patterns, as indicated by Spearman correlation analysis. The high-risk group exhibited diminished predicted response to immunotherapy (TIDE scores). Drug sensitivity analysis identified four compounds—Dasatinib-51, WH-4-023-56, TWS-119-366, and LDN-193189-478—with elevated efficacy in high-risk CRC cases. PCOLCE2 expression was significantly reduced in CRC tissues. Functional assays revealed that PCOLCE2 knockdown did not substantially affect cell proliferation but significantly impaired invasion and migration in CRC cells, increased apoptosis, and suppressed both glutamine uptake and glutamate production—highlighting its oncogenic role. CONCLUSION: Six GMRGs—SRPX, CXCL1, GPX3, PCOLCE2, CLU, and SEMA3E—were identified as key components of a robust prognostic model for CRC. These findings offer valuable insights into CRC pathogenesis and potential therapeutic strategies. Notably, this study provides the first evidence implicating PCOLCE2 as a tumor-promoting factor in CRC.

Glutamine↗

PubMed2005

[Colorectal cancer patients treated in surgical departments of the Lublin region--clinical and pathologic features obtained from the Lublin Colorectal Cancer Registry].

Introduction of regional screening programs should be based upon the coherency of epidemiological data and the selection of specific patient groups. This would have significantly reduced costs and improve medical benefits. The aim of the study was to determine the number of patients with colorectal cancer that underwent surgical treatment and achieving clinical and/or pathological data which would be the basis in planning regional screening programs. The data of 1,770 patients that underwent surgical treatment during 1991-2001, in the province of Lublin was attained from the assessment of questionnaires. The results show an increase in morbidity of colorectal cancer in patients over 50 years old in both sexes, irrespectively to primary tumor localization. In 78% of the patients tumors were localized in the distal region of the splenic flexure of colon. The frequency in occurrence of advanced colorectal cancer, morbidity and peri-operative mortality increased due to the patients older age. The results of this research suggest the need to proceed with screening programs in patients over 50 years old with the use of flexible sigmoidoscopy as a method which diagnoses approximately 80% of colorectal cancers.

Aged↗

PubMed1995

[Clinical study of ambulatory cancer chemotherapy for advanced colorectal cancer].

To evaluate ambulatory cancer chemotherapy, the clinical response, toxicities and survival time were analysed among 32 patients with non-curative or recurrent colorectal cancer who were treated by l-Leucovorin (l-LV) plus 5-fluorouracil for the past four years. Twenty-nine patients were treated with 5-FU (370 mg/m2) plus l-LV (10-100 mg/m2) for 5 consecutive days and a 23-day interval between treatments. Three patients were treated with l-LV (250 mg/m2) administered as a two-hour infusion and 5-FU (600 mg/m2) intravenous push midinfusion weekly for 6 weeks of an 8-week cycle. Partial response (PR) was observed in 9 patients (28%), no change (NC) in 18. One-year survival ratio was 61% and 4 of 32 patients survived at the end of this study. The median survival time was 14 months. Although stomatitis, nausea/vomiting, diarrhea, leukopenia and pigmentation were noted, no severe side effects were observed. These results suggested that l-LV plus 5-FU therapy might be a useful ambulatory cancer chemotherapy for patients with advanced colorectal cancer.

Adult↗

PubMed2002

A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer.

Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility. In a multicenter case-control study, 490 colorectal cancer patients and 593 controls (433 matched case-control pairs) were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1, GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2 (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case-control analysis identified alleles associated with higher colorectal cancer risk as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for GSTM1*2/*2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the CYP2A6*2 (OR = 0.51, 95% CI 0.28-1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52-0.98) and the EPHX1(His113) alleles were associated with reduced cancer risk. We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens. This data suggests that heterocyclic amines do not play an important role in the aetiology of colorectal cancer but that exposure to other carcinogens such as polycyclic aromatic hydrocarbons may be important determinants of cancer risk.

Adenocarcinoma↗

PubMed2003

SLIT2 axon guidance molecule is frequently inactivated in colorectal cancer and suppresses growth of colorectal carcinoma cells.

We have shown recently that SLIT2 has tumor suppressor activity and that it is epigenetically silenced in >40% of lung and breast tumors. In this study, we have analyzed the methylation status of SLIT2 in primary colorectal cancers and matching normal colorectal mucosa. SLIT2 promoter region methylation was found in 23 (72%) of 32 primary colorectal cancers. In contrast, normal colorectal mucosa from the same patients exhibited significantly lower levels of SLIT2 promoter region hypermethylation. SLIT2 methylation was reversed and expression restored by treating colorectal tumor cell lines with the demethylating agent 5-aza-2-deoxycytidine. Loss of heterozygosity at D4S1546 marker, which maps within 100 kb of the SLIT2 gene, was observed in 39% of the methylated tumors. Furthermore, SLIT2 epigenetic silencing was independent of ROBO1/p16/RASSF1A hypermethylation. The presence of SLIT2 methylation was also independent of the presence of K-RAS mutations. Ectopic expression of SLIT2 diminished the ability to form colonies in two colorectal tumor cell lines. In addition, conditioned medium from SLIT2-transfected COS-7 cells reduced cell growth and induced apoptosis in SW48 colorectal tumor cell line. In conclusion, SLIT2 is an excellent candidate tumor suppressor gene for colorectal cancer.

Apoptosis↗

PubMed2003

Quality control in colorectal cancer screening: systematic microbiological investigation of endoscopes used in the NORCCAP (Norwegian Colorectal Cancer Prevention) trial.

BACKGROUND: Endoscopic colorectal cancer (CRC) screening is currently implemented in many countries. Since endoscopes cannot be sterilised, the transmission of infectious agents through endoscopes has been a matter of concern. We report on a continuous quality control programme in a large-scale randomised controlled trial on flexible sigmoidoscopy screening of an average-risk population. Continuously, throughout a two-year screening period, series of microbiological samples were taken from cleaned ready-to-use endoscopes and cultured for bacterial growth. RESULTS: 8573 endoscopies were performed during the trial period. Altogether, 178 microbiological samples (2%) were taken from the biopsy channels and surfaces from the endoscopes. One sample (0.5%) showed faecal contamination (Enterobacter cloacae), and 25 samples (14%) showed growth of environmental bacteria. CONCLUSIONS: Growth of bacteria occurs in a clinical significant number of samples from ready-to-use endoscopes. Pathogenic bacteria, however, were found only in one sample. Improvement of equipment design and cleaning procedures are desirable and continuous microbiological surveillance of endoscopes used in CRC screening is recommended.

Bacteria↗

PubMed2005

[Clinical study of ambulatory patient cancer chemotherapy for advanced colorectal cancer].

To evaluate ambulatory patient cancer chemotherapy, the clinical response, toxicities and survival time were analysed among 19 patients with non-curative or recurrent colorectal cancer who were treated by Uracil/Tegafur (UFT) plus oral Leucovorin (UZEL) for the past 2 years. The patients were administered UFT (300 mg/m2/day) and UZEL (75 mg/body/day) for 28 days with a one-week interval every 35 days as one course.A partial response (PR) was observed in 6 patients (31.6%) and stable disease (SD) in 8. The median survival time was 16 months. Although nausea/vomiting, diarrhea and leucopenia were noted, no severe side effects were observed. These results suggested that UFT plus Leucovorin therapy might be a useful cancer chemotherapy for ambulatory patients with advanced colorectal cancer.

Administration, Oral↗