Analysis of Intestinal Microflora Combined With DNA Methylation in Stool to Detect Colorectal Cancer (IMMDC)

March 6, 2020 updated by: WEIDONG LIU，MD

Analysis of Intestinal Microflora Combined With DNA Methylation in Stool to Detect Colorectal Cancer: a Study Protocol for Colorectal Neoplasms Screening

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.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Observational

Enrollment (Anticipated)

500

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • China
    • Hunan
      • Changsha, Hunan, China, 410000
        • Recruiting
        • Xiangya Hospital of Central South University
        • Principal Investigator:
          • Jie Chen
        • Contact:
        • Principal Investigator:
          • mingmei Liao, PhD
        • Principal Investigator:
          • xi Xie, PhD
        • Principal Investigator:
          • zhan Qu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

This program was performed in Xiangya Hospital(Still recruiting), Changsha, Hunan, China.

Only participants who received a colonoscopy were enrolled

Description

Inclusion Criteria:

  • colonoscopy revealing colon or rectal tumor and biopsy-confirmed adenocarcinoma or adenoma.
  • no chemotherapy or surgery, and no history of other cancer.
  • must be able to understand and be willing to sign informed consent.
  • Healthy controls don't have tumors and history of cancer.

Exclusion Criteria:

  • Those who not willing to provide specimens or answer questionnaires before the study began.
  • People whose stool samples does not meet the requirements.
  • People who are unwilling to sign written informed consent or follow a research protocol.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Control Group
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
Fecal microbiota detection and exfoliated cell gene detection
Test Group
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Diagnostic efficacy of colorectal cancer model in Chinese people
Time Frame: 2 years
the difference in intestinal flora and gene methylation between CRC patients and healthy individuals.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of diet on intestinal flora and DNA methylation in Chinese people
Time Frame: 3 years
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)
3 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effect of cholecystectomy on intestinal flora and methylation
Time Frame: 3 years
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.
3 years
Effects of intestinal microflora and DNA methylation under different stool characteristics
Time Frame: 3 years-4years
Classification of feces using the Bristol Stool Scale method.Scores from 1 to 7, lower scores indicate harder stool.
3 years-4years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

WEIDONG LIU，MD

Collaborators

Natural Science Foundation of Hunan Province

Investigators

  • Study Chair: weidong Liu, PhD, Xiangya Hospital of Central South University
  • Study Director: mingmei Liao, PhD, Xiangya Hospital of Central South University
  • Principal Investigator: xi Xie, PhD, Xiangya Hospital of Central South University
  • Principal Investigator: jie Chen, PhD, Xiangya Hospital of Central South University
  • Principal Investigator: zhan Qu, PhD, Xiangya Hospital of Central South University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2018

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

December 1, 2021

Study Registration Dates

First Submitted

November 5, 2019

First Submitted That Met QC Criteria

March 6, 2020

First Posted (Actual)

March 10, 2020

Study Record Updates

Last Update Posted (Actual)

March 10, 2020

Last Update Submitted That Met QC Criteria

March 6, 2020

Last Verified

March 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CCRS-2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

IPD Plan Description

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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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