An observational study in Gastrointestinal Microbiome, DNA Methylation and Colorectal Neoplasms, sponsored by WEIDONG LIU，MD. Status unknown at 1 site in China. Open to participants aged 18 Years to 75 Years. Per ClinicalTrials.gov, last updated 2020-03-10.
Sponsored by WEIDONG LIU，MD · Observational
Introduction: Colorectal cancer (CRC) has the third highest incidence rate and the fourth mortality rate in the world. Traditional colonoscopy as an invasive examination method cannot be widely used in screening for colorectal neoplasia. The fecal immunochemical test has some limitations in sensitivity. Also, race and regional differences may affect results. Abnormality in the composition of the gut microbiota has been implicated as a potentially important etiologic factor in the initiation and progression of colorectal cancer. Analyzing fecal flora and exfoliated cell genes may represent a new screening tool for colorectal cancer.This research aims to use 16S rRNA to compare differences in fecal flora between colorectal cancer patients and healthy controls. These data combined with DNA findings of fecal exfoliated cells may further clarify this difference to build a model for screening early colorectal cancer in Chinese people.
Methods and analysis: In total, 300 patients with positive colonoscopy results and 200 health controls will be recruited. All participants will complete an information form and questionnaires. Fecal samples will be examined by 16S rRNA analysis. Gene methylation levels will be detected in fecal exfoliated cells. Models of related intestinal microbiota and methylation genes will be built. Receiver operating characteristic (ROC) curve analysis will be used to select some models with appropriate sensitivity and specificity.The models will be further validated by multicenter studys.
Introduction： Colorectal cancer (CRC) has the third highest incidence rate and the fourth mortality rate in the world. In China, CRC is the fifth leading cause of cancer deaths. Age-standardized incidence rates in CRC have shown an upward trend.A Westernized lifestyle, particularly physical inactivity, and an increase in the prevalence of obesity in recent decades in China may explain the increase in CRC incidence .
The 5-year survival rate for people with CRC is 65%. Survival rates for CRC can vary depending on various factors, particularly cancer stage. The 5-year survival rate with localized-stage CRC is 90%. About 39% of patients are diagnosed at this early stage. Because of the lack of typical clinical symptoms, early CRC is difficult to detect, and most patients are already in the advanced stage when CRC is diagnosed, thus missing the best intervention stage. Therefore, early detection and early treatment are effective means to reduce the mortality with CRC. Screening has benefits, including diagnosis at an earlier stage, reduced incidence of CRC and reduced mortality.
At present, the main screening methods for CRC are fecal occult blood test and colonoscopy. Colonoscopy is the gold standard for screening for CRC. However, traditional colonoscopy, an invasive examination method, cannot be widely used in screening for colorectal neoplasia.
Fecal samples are easily obtained.Using feces to screen CRC is the current research consensus. According to the most updated Asia Pacific consensus recommendations for CRC screening,FIT(fecal immunochemical test) is used to select high-risk patients for colonoscopy. FIT has also been widely used in other world regions . The sensitivity of FIT is limited (0.79; 95% CI, 0.69-0.86), and a recent systematic meta-analysis showed wide variation in sensitivity among studies . In addition, race and regional differences may affect test results. Therefore, the early screening methods which is non-invasive, highly sensitive and suitable for Chinese people are needed.
Detection of molecular biomarkers in feces for non-invasive diagnosis of CRC may be a promising alternative to detecting blood/plasma biomarkers in current clinical settings. Abnormalities in the composition of the gut microbiota have been implicated as potentially important causes of CRC. With the widespread use of metagenomic sequencing and pyrosequencing in intestinal microbiota research, more bacteria have been found positively associated with CRC incidence. In a recent study, 16S rRNA sequencing was used to classify microbial communities in human intestinal mucosa at different stages of colorectal tumorigenesis, and Fusobacterium was found enriched in colorectal tumors.
For CRC, the main process of benign polyps becoming malignant tumors is the accumulation of genetic and epigenetic alterations that transform colonic epithelial cells into colon adenocarcinoma cells. These cells are continuously shed into colonic lumen and mixed with the stool. During tumor formation, epigenetic changes may occur earlier than mutations. Deregulation of epigenetic mechanisms plays an important role in cancer. Most epigenetic changes in cancer are triggered by genomic alterations in specific genes that are involved in controlling one of the epigenetic mechanisms.Aberrant DNA methylation of tumor suppressor genes induces abnormal expression of downstream genes, which is an important step in the process of tumorigenesis.The methylation status of DNA changes during CRC progression. A number of gene methylation abnormalities associated with CRC discovered in recent studies include SFRP2, SEPT9, BMP3, NDRG4, and SPG20. In addition, some gene mutations are related to CRC. For example, TP53 and KRAS mutations are common in CRC.
In previous research the investigators found that SEPT9, NDRG4, and SDC2 had higher frequency and level of methylation in tumors than in normal or non-tumor adjacent CRC tissues, indicating that these methylated genes may have diagnostic potential for CRC screening. However, BMP3 had very limited contribution to detection accuracy in stool samples. Furthermore, the combination of methylated SEPT9, NDRG4, and SDC2 showed high feasibility of detection of CRC and adenoma and further study showed better performance in detecting CRC than adenoma. Our research also demonstrates differences in fecal genes between different ethnic groups.
This research aims to detect intestinal microbiota differences in stool by 16S rRNA analysis between CRC patients and healthy controls. It will combine DNA analysis of fecal exfoliated cells to further clarify this difference to build some models for screening early colorectal cancer in Chinese people. At the same time, the research will also study the impact of Chinese eating habits on Intestinal Microflora.
9,365 studies on the registry are indexed under Neoplasms; 2,489 are open to participants now.
This study's planned enrollment of 500 is above the median of 204 across 1,683 observational studies indexed under Neoplasms.
Browse Neoplasms studies →WEIDONG LIU，MD is the lead sponsor of 2 studies on the registry; 1 is open to participants now.
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This program was performed in Xiangya Hospital(Still recruiting), Changsha, Hunan, China.
Only participants who received a colonoscopy were enrolled
Exclusion Criteria:
Healthy controls must be 18-75 years old with no tumors and no history of cancer.
Other: Fecal microbiota detection and exfoliated cell gene detection
Inclusion criteria in the experimental group are age 18-75 years old, colonoscopy revealing colon or rectal tumor, biopsy-confirmed adenocarcinoma or adenoma, no chemotherapy or surgery, and no history of other cancer. Both groups must be able to understand and be willing to sign informed consent.
Other: Fecal microbiota detection and exfoliated cell gene detection
Fecal microbiota detection and exfoliated cell gene detection
Diagnostic efficacy of colorectal cancer model in Chinese people
the difference in intestinal flora and gene methylation between CRC patients and healthy individuals.
Time frame: 2 years
Effect of diet on intestinal flora and DNA methylation in Chinese people
Investigate the frequency (e.g. ,"how many times a week"), quantity (e.g. ,"g") and types of food by semi-quantitative food frequency questionnaire (SQFFQ)
Time frame: 3 years
Effect of cholecystectomy on intestinal flora and methylation
All participants complete an information form gathering data on age, sex, occupation, etc. At the same time, we will also collect the history and time of cholecystectomy.
Time frame: 3 years
Effects of intestinal microflora and DNA methylation under different stool characteristics
Classification of feces using the Bristol Stool Scale method.Scores from 1 to 7, lower scores indicate harder stool.
Time frame: 3 years-4years
Plan to share: Undecided — Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.The data will be saved in digital form in the excel form and the image will be saved in PNG format.All data will be kept by Professor Wei-dong Liu.
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WEIDONG LIU，MD