Colorectal cancer (CRC) is one of the most common malignancies and leading cause of cancer-related deaths in the world. However, it may be treated effectively by surgical removal of the cancerous tissue if detected at early stages. Conventional tools for screening CRC are either invasive or inaccurate. Therefore, there is an urgent need to develop a reliable screening tools for CRC to significantly reduce its morbidity. In this regard, a novel DNA markers-based detection in stool is emerging as a promising approach.
Colorectal Neoplasms/*diagnosis/*genetics ; Epigenesis, Genetic/*genetics ; *Feces ; Genetic Markers/*genetics ; Tumor Markers, Biological/genetics

Omics docking has become a hot spot in oncology research, which is used to screen specific biomarkers for the establishment of molecular classification in the treatment and/or prognosis of diseases, especially in cancer research. Colorectal cancer (CRC) is one of the common malignant tumors, the traditional diagnosis and treatment of which depends on clinical manifestations, classic pathological and imaging examination. In clinical pathology, completely different fates and prognoses were observed in CRC patients with the same type, at the same stage, and even with the same treatment. It is critical to use the omics docking strategy to select molecular biomarkers for early diagnosis and to assess the prognosis of CRC, to further standardize molecular classification model, and to guide individual treatment of CRC.
Animals ; Biomarkers, Tumor ; genetics ; metabolism ; Colorectal Neoplasms ; classification ; diagnosis ; genetics ; Genomics ; Humans ; Proteomics

The molecular genetics of colorectal carcinomas are among the best understood of common human cancers. Three inter-related molecular pathways are involved. The chromosomal instability pathway begins with inactivation of the APC/beta-catenin genes followed by activation of oncogenes and inactivation of additional suppressor genes, commonly with high frequency of allelic losses, cytogenetic abnormalities. The microsatellite instability pathway begins with inactivating one of a group of genes responsible for DNA nucleotide mismatch repair leading to extensive mutations in both repetitive and non-repetitive DNA sequences with low frequencies of allelic losses and rare alteration of tumor DNA content. Finally, the CpG island methylation pathway involves inactivation of genes by methylation of cytosines in promoter regions to silence gene expression without DNA sequence alterations. Molecular genetics have the potential for clinical applications. Combination of genetic classification of high levels of microsatellite instability (MSI-H), gene expression analysis of mismatch repair genes and subsequent mutation analysis of inactivated genes can be used as an effective method for the identification of hereditary nonpolyposis colorectal carcinoma patients. Molecular genetic alterations have been proposed to be of prognostic value, including allelic deletion on chromosome 18q, and on chromosome 17p. MSI-H has been reported as a marker for better prognosis. Individualizing chemoradiation by use of predictive markers for response or resistance to therapy is important in patients with advanced disease or candidacy for adjuvant therapy.
Chromosomal Instability ; Colorectal Neoplasms/diagnosis/*genetics/pathology ; English Abstract ; Humans ; Microsatellite Repeats

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited disease associated with germ-line mutations in mismatch repair genes and microsatellite instability. This article reviews the molecular biology and clinical pathology of HNPCC.
Colorectal Neoplasms, Hereditary Nonpolyposis ; diagnosis ; genetics ; pathology ; DNA Mismatch Repair ; Humans ; Microsatellite Instability

Elderly patients with colorectal cancer have different clincopathological characteristics from younger patients. Colorectal cancers tend to localize in the proximal colon, from cecum to the splenic flexure in the elderly patients. Changes in the stools, rectal bleeding or black stool, abdominal pain, fatigue, weight loss and anemia are the common symptoms. Analysis showed that age is one of independent risk factors for lower completion rates of colonoscopy. Therefore, the choice of diagnosis methods in elderly patients should be careful. Achieving a clear diagnosis and avoiding complications should be considered at the same time. Most colorectal cancers in elderly are highly and moderately differentiated adenocarcinomas and locally advanced, and have less lymphatic and blood metastasis. The proportion of poorly differentiated adenocarcinoma increases with the increase of age, which should be concerned. Multiple colorectal cancers and colorectal cancer with extra-colorectal malignancy are not rare in the elderly patients. The common extra-colorectal tumors consist of gastric cancer, lung cancer, biliary carcinoma, pancreas cancer and malignancy from blood system. Molecular events, such as mutations of KARS, BRAF, TP53 and deficiency of DNA mismatch repair, are more frequent in elderly colorectal cancer patients. Many factors have impact on treatment decision in elderly patients with colorectal cancer, including age, comorbidities, physiological functions of organs and willingness of patients and their relatives. Although surgery is still the main treatment, the proportion of radical surgery is lower and emergency surgery is higher as compared to younger patients. With the development of minimally invasive surgical techniques and advances in anesthesia and perioperative management, laparoscopic surgery has become widespread in elderly patients with colorectal cancer. In addition, more attention should be paid to adjuvant therapy. Comprehensive individualized treatment plan should be taken to improve outcomes.
Adenocarcinoma ; pathology ; Aged ; Colonoscopy ; Colorectal Neoplasms ; diagnosis ; genetics ; pathology ; surgery ; Humans ; Laparoscopy ; Mutation ; Risk Factors

BACKGROUND: Microsatellite instability (MSI) is a key biomarker for cancer immunotherapy and prognosis. Integration of MSI testing into a next-generation-sequencing (NGS) panel could save tissue sample, reduce turn-around time and cost, and provide MSI status and comprehensive genomic profiling in single test. We aimed to develop an MSI calling model to detect MSI status along with the NGS panel-based profiling test using tumor-only samples. METHODS: From January 2019 to December 2020, a total of 174 colorectal cancer (CRC) patients were enrolled, including 31 MSI-high (MSI-H) and 143 microsatellite stability (MSS) cases. Among them, 56 paired tumor and normal samples (10 MSI-H and 46 MSS) were used for modeling, and another 118 tumor-only samples were used for validation. MSI polymerase chain reaction (MSI-PCR) was performed as the gold standard. A baseline was built for the selected microsatellite loci using the NGS data of 56 normal blood samples. An MSI detection model was constructed by analyzing the NGS data of tissue samples. The performance of the model was compared with the results of MSI-PCR. RESULTS: We first intersected the target genomic regions of the NGS panels used in this study to select common microsatellite loci. A total of 42 loci including 23 mononucleotide repeat sites and 19 longer repeat sites were candidates for modeling. As mononucleotide repeat sites are more sensitive and specific for detecting MSI status than sites with longer length motif and the mononucleotide repeat sites performed even better than the total sites, a model containing 23 mononucleotide repeat sites was constructed and named Colorectal Cancer Microsatellite Instability test (CRC-MSI). The model achieved 100% sensitivity and 100% specificity when compared with MSI-PCR in both training and validation sets. Furthermore, the CRC-MSI model was robust with the tumor content as low as 6%. In addition, 8 out of 10 MSI-H samples showed alternations in the four mismatch repair genes ( MLH1 , MSH2 , MSH6 , and PMS2 ). CONCLUSION MSI status can be accurately determined along the targeted NGS panels using only tumor samples. The performance of mononucleotide repeat sites surpasses loci with longer repeat motif in MSI calling.
Humans ; Microsatellite Instability ; Colorectal Neoplasms/diagnosis* ; Microsatellite Repeats/genetics* ; DNA Mismatch Repair

Hereditary syndromes cause approximately 5 to 15% of overall colorectal cancer (CRC) cases. Hereditary CRC is conventionally divided into two major categories: hereditary non-polyposis colorectal cancer (HNPCC) and those related to polyposis syndromes including familial adenomatous polyposis (FAP), Peutz-Jegher syndrome (PJS), and juvenile polyposis (JP). The screening for the cancer and methods of treatment applied to patients with hereditary CRC are quite different from those applied to the general population. The genes responsible for these syndromes has recently identified, as a result, genetic testing has become the most important determining factor in clinical decisions. Germ-line mutation of the APC gene induces FAP, an autosomal dominant disorder, characterized by the development of hundreds to thousands of colonic adenomas. CRC appears in almost all affected individuals by the time they are 50 years of age. An affected individual should undergo colectomy by his/her late teens. Furthermore, according to the findings of genetic testing, at-risk family members also need endoscopic surveillance and surgery. Recently, a mutation on the MYH gene is increasingly being investigated in patients with multiple polyps, and autosomal recessive MYH polyposis is considered to be a new category of polyposis. More common than FAP, HNPCC is caused by germ-line mutations in DNA mismatch repair genes, mainly MLH1 and MSH2. Although there is no polyposis, polyps seem to be more villous and dysplastic and appear to grow rapidly into CRCs. The aggregate lifetime risk of CRC is about 80% for mutation carriers. The risk for other types of cancer, such as endometrial, ovarian, small bowel, and transitional cell cancer, is also increased. The Amsterdam criteria and Bethesda guidelines are the best-known tools for diagnosis and genetic testing, and colectomy followed by endoscopic follow-up is the standard treatment. PJS and JP are reported to be characterized by hamartomatous polyps throughout the GI tract and germ-line mutations in the STK11 gene (PJS) and the DPC4/BMPR1A gene (JP).
Adenomatous Polyposis Coli/*genetics ; Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis/*genetics ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Intestinal Polyposis/diagnosis/*genetics ; Peutz-Jeghers Syndrome/diagnosis/*genetics

Colorectal cancer screening dates to the discovery of pre-cancerous adenomatous tissue. Screening modalities and guidelines directed at prevention and early detection have evolved and resulted in a significant decrease in the prevalence and mortality of colorectal cancer via direct visualization or using specific markers. Despite continued efforts and an overall reduction in deaths attributed to colorectal cancer over the last 25 years, colorectal cancer remains one of the most common causes of malignancy-associated deaths. In attempt to further reduce the prevalence of colorectal cancer and associated deaths, continued improvement in screening quality and adherence remains key. Noninvasive screening modalities are actively being explored. Identification of specific genetic alterations in the adenoma-cancer sequence allow for the study and development of noninvasive screening modalities beyond guaiac-based fecal occult blood testing which target specific alterations or a panel of alterations. The stool DNA test is the first noninvasive screening tool that targets both human hemoglobin and specific genetic alterations. In this review we discuss stool DNA and other commercially available noninvasive colorectal cancer screening modalities in addition to other targets which previously have been or are currently under study.
Biomarkers, Tumor/genetics ; Colorectal Neoplasms/*diagnosis/genetics ; DNA/analysis ; Early Detection of Cancer/*methods ; *Feces ; Humans ; Mass Screening/*methods

Objective To verify the expressions of genes associated with colorectal cancer with hyperglycemia and evaluate their diagnostic values.Methods Tumor tissues,distal normal intestinal mucosa,and peripheral blood samples were harvested from 109 colorectal cancer patients and peripheral blood samples from 30 diabetes patients and 30 healthy volunteers. The mRNA expressions of glucose regulated protein 78 (GRP78),NADPH oxidase-1 (NOX1),carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5),heat shock protein 60 (HSP60),and histone deacetylase 1(HDAC1) were detected by real-time quantitative polymerase chain reaction. The correlation between the gene expressions and clinicopathological parameters in colorectal cancer patients were analyzed using Pearson's correlation analysis. Diagnostic test accuracy evaluation was used to calculate the sensitivity,specificity,accuracy,predictability,Youden index,and likelihood ratio of serum gene expressions in colorectal cancer patients,and the receiver operating characteristic (ROC) curves were drawn. The area under the ROC curve was calculated to evaluate the diagnostic efficiency of the combined detection of multiple genes.Results The mRNA levels of GRP78 (P=0.001),NOX1 (P=0.022),CEACAM5 (P=0.000),HSP60 (P=0.044),and HDAC1 (P=0.047) were positively correlated with the fasting blood glucose level. The mRNA expressions of NOX1 (P=0.000,P=0.008) and HDAC1 (P=0.000,P=0.037) in tissues and serum were significantly higher in colorectal cancer patients than in patients with normal blood glucose levels. The NOX1 mRNA expression was positively correlated with the diameter of colorectal cancer (P=0.013),and the HDAC1 mRNA expression was significantly correlated with the tumor site (P=0.049),depth of primary tumor invasion (P=0.025),and TNM stage (P=0.042). The areas under the ROC curves of NOX1,CEACAM5,and HDAC1 were 0.931,0.852,and 0.860 respectively (all P=0.000). The specificity,accuracy,and negative predictive value of NOX1,HDAC1 mRNA expression in colorectal cancer patients with hyperglycemia were all above 90%. The diagnostic sensitivity and specificity of the combined detection of NOX1,CEACAM5,and HDAC1 were 98.82% and 99.93%,respectively.Conclusion Combined detection of genes associated with colorectal cancer accompanied by hyperglycemia can improve the diagnostic efficiency of early screening.
Biomarkers, Tumor ; genetics ; Carcinoembryonic Antigen ; genetics ; Case-Control Studies ; Colorectal Neoplasms ; complications ; diagnosis ; genetics ; Diabetes Mellitus ; genetics ; GPI-Linked Proteins ; genetics ; Heat-Shock Proteins ; genetics ; Histone Deacetylase 1 ; genetics ; Humans ; Hyperglycemia ; complications ; diagnosis ; genetics ; NADPH Oxidase 1 ; genetics ; ROC Curve

OBJECTIVETo investigate the expression of the interferon-induced transmembrane-1 (IFITM1) gene in colorectal cancer (CRC) tissue and the serum anti-IFITM1 antibody responses of the patients and assess their value in clinical diagnosis of CRC.

METHODSSemi-quantitative RT-PCR was performed to detect IFITM1 mRNA expression in the specimens of normal colonic mucosa, CRC tissue, inflammatory polyps, adenomatous polyps, gastric cancer, esophageal carcinoma and liver cancer tissues. Serum samples were collected from the patients to detect anti-IFITM1 antibody responses using Western blotting. The clinicopathological features of the carcinoma expressing IFITM1 gene were analyzed.

RESULTSIFITM1 mRNA was expressed in 47.4 % (18/38) of the CRC specimens, a rate significantly higher than that in adenomatous polyps [15% (3/20)] and gastric cancer [4.8% (1/21)]; no obvious IFITM1 expression was found in normal colonic mucosa, inflammatory polyp, esophageal carcinoma or liver cancer tissues (P<0.001 or P<0.05). IFITM1 mRNA was strongly expressed in CRC at the expression level of 0.8048-/+0.2273, which was significantly higher than that in adenomatous polyps (0.4447-/+0.0989, P<0.001). No anti-IFITM1 antibody response was detected in healthy human sera, but in the CRC patients, the serum antibody response was detected at the rate of 36.8% (14/38), significantly higher than the rate of 9.5% (2/21) in gastric cancer (P<0.05). No antibody response was detected in esophageal carcinoma, liver cancer, inflammatory polyp or adenomatous polyps. Most of the IFITM1-expressing CRC had a diameter exceeding 5 cm, often invading the serous membrane with metastasis to the lymph nodes and the distant organs; these tumors were identified mostly as well-differentiated adenocarcinoma in Dukes stage C or D.

CONCLUSIONIFITM1 gene may play an important role in the pathogenesis, development and metastasis of CRC, and may serve as a potential biomarker for clinical diagnosis of CRC.

Antibodies ; blood ; Antigens, Differentiation ; Biomarkers, Tumor ; genetics ; metabolism ; Colorectal Neoplasms ; diagnosis ; genetics ; Humans ; Membrane Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics ; immunology ; metabolism