Diagnosis of Lynch Syndrome Based on Next-generation Sequencing in Colorectal Cancer

Diagnosis of Lynch Syndrome Based on the Colorectal Core™ Platform in Colorectal Cancer Patients With the Loss of Staining by Immunohistochemistry (IHC) of Any of the Mismatch Repair (MMR) Proteins: An Open-label and Multi-center Study

The purpose of this study is to determine the proportion of patients diagnosed with Lynch syndrome in colorectal cancer patients with the loss of staining by immunohistochemistry (IHC) of any of the mismatch repair (MMR) proteins. Besides, this study aims to test the specificity and the sensitivity of detecting microsatellite instability (MSI) by next-generation sequencing, and to find out the consistency between IHC and MSI in colorectal cancer patients in China. In addition, researchers want to analyze the clinical characteristics and germline mutation of Lynch syndrome in Chinese population.

Study Overview

• Status: Completed
• Conditions: Lynch Syndrome
• Intervention / Treatment: Other: next-generation sequencing

Detailed Description

1. Detect microsatellite instability (by next-generation sequencing and PCR capillary electrophoresis) and germline mutation (by next-generation sequencing) in probands.
2. Analyze the test outcome with clinical and family information to evaluate the germline mutation status preliminarily: likely pathogenic germline mutation, variant of uncertain significance, non-pathogenic germline mutation.
3. Verify the germline mutation in blood relatives whose proband has known likely pathogenic germline mutation or variant of uncertain significance.
4. Diagnose pathogenic germline mutation and non-pathogenic germline mutation based on clinical characteristics, family information and germline mutation test outcomes (including the outcomes of probands and blood relatives). Diagnose Lynch syndrome and the pathogenic germline mutation carriers in the included population.
5. Analyze the specificity and the sensitivity of detecting microsatellite instability (MSI) by next-generation sequencing; and analyze the consistency between IHC and MSI.
6. Analyze the clinical characteristics and germline mutation of Lynch syndrome in Chinese population.

• Study Type: Observational
• Enrollment (Actual): 311

Contacts and Locations

Study Locations

• China
  • Fujian
    • Fuzhou, Fujian, China
      • Fujian Medical University Cancer Hospital
  • Guangdong
    • Guangzhou, Guangdong, China
      • Sun Yat-sen University Cancer Center
  • Tianjin
    • Tianjin, Tianjin, China
      • Tianjin Medical University Cancer Institute and Hospital
  • Yunnan
    • Kunming, Yunnan, China
      • Yunnan Cancer Hospital
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Zhejiang Cancer Hospital
    • Hangzhou, Zhejiang, China
      • Affiliated Hangzhou First People's Hospital
  • Zhejinag
    • Hangzhou, Zhejinag, China, 310009
      • YUANYING

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

The probands will be selected from colorectal cancer patients with the loss of staining by immunohistochemistry of any of the mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2).

The blood relatives verifying germline mutation will be selected from whose probands have germline mutation(s).

Description

For probands, the inclusion criteria:

All of the following four points should be satisfied:

• Histological diagnosis of colorectal cancer;
• With the loss of staining by immunohistochemistry of any of the mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2);
• With sufficient tumor tissue and normal tissue to test;
• Agree to provide basic information, clinical information and family history of cancer information.

For probands, the exclusion criteria:

• With at least one blood relative with known pathogenic germline mutation(s).

For blood relatives verifying germline mutation, the inclusion criteria:

All of the following three points should be satisfied:

• First- to second-degree blood relatives of probands with germline mutation(s).
• With Sufficient tumor tissue and normal tissue to test.
• Agree to provide basic information, clinical information and family history of cancer information.

For blood relatives verifying germline mutation, the exclusion criteria:

• Blood relatives who refuse to test.

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathogenic germline mutation	Pathogenic germline mutation using next-generation sequencing with a targeted panel.	Upon completion of study, on average 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Variant of uncertain significance of germline mutation	Variant of uncertain significance of germline mutation using next-generation sequencing with a targeted panel.	Upon completion of study, on average 2 years.

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: Guangzhou Burning Rock Medical Examination Institute Co., Ltd.
• Investigators: Principal Investigator: Ying Yuan, MD, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): February 28, 2017
• Primary Completion (Actual): July 31, 2018
• Study Completion (Actual): July 31, 2018

Study Registration Dates

• First Submitted: January 23, 2017
• First Submitted That Met QC Criteria: February 7, 2017
• First Posted (Estimate): February 8, 2017

Study Record Updates

• Last Update Posted (Actual): July 15, 2021
• Last Update Submitted That Met QC Criteria: July 14, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: next-generation sequencing; immunohistochemistry; Lynch Syndrome; mismatch repair; microsatellite instability
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Metabolic Diseases; Neoplasms; Neoplasms by Site; Disease; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Genetic Diseases, Inborn; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; DNA Repair-Deficiency Disorders; Syndrome; Colorectal Neoplasms, Hereditary Nonpolyposis
• Other Study ID Numbers: RSKY2016019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided