Around 1 in 500 people in the UK carry Lynch syndrome, a genetic condition that dramatically raises their risk of colorectal and other cancers, yet only 5% of them know it. This evidence map will assess whether enough evidence exists to justify a full review of how to screen the asymptomatic relatives of colorectal cancer patients who have Lynch syndrome. Cascade testing—testing family members once a case is found—could catch many more carriers early, allowing them to access surveillance and risk-reducing strategies that improve outcomes. The map will systematically search for national and international guidelines on targeted screening, compare the accuracy of different genetic tests for relatives, and gather data on how often colorectal cancer develops in people with confirmed mismatch repair gene mutations. If the evidence is sufficient, the UK National Screening Committee could commission a sustained review that might eventually lead to formal recommendations for cascade testing. That would shift Lynch syndrome from a condition caught mostly by chance to one systematically identified through families, quietly preventing cancers in people who otherwise would not know they were at risk.
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Background: Lynch syndrome (LS) is a cancer predisposition condition. While individuals with LS have no signs or symptoms of it, they have a lifetime colorectal cancer (CRC) risk of between 10% and 80%. They also have an increased risk of other cancers (e.g. endometrial, ovarian, pancreatic, gastric, urothelial and brain cancers). LS is an autosomal dominant syndrome which is caused by a single germline pathogenic gene variant in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) or in the epithelial cellular adhesion molecule (EPCAM) gene (responsible for silencing MSH2 expression). MMR is a system that maintains the stability of DNA by recognising and repairing errors that arise during replication and recombination. As two alleles (versions) of each of the MMR genes are inherited, people with LS can produce MMR proteins. If the functional (non-pathogenic) copy becomes inactivated, LS individuals lose functionality of the MMR system which leads to a deficiency in the corresponding MMR protein and errors in the DNA accumulate leading to an increased risk of developing cancer. In the UK, it is estimated that approximately 1 in 500 people have LS, with only 5% being diagnosed. NICE DG27 Diagnostic Guideline recommends all CRC patients are tested for Lynch syndrome, typically using tumour tests followed by germline testing. Diagnosis of LS enables surveillance for subsequent cancers and for risk-reducing strategies to be offered. Screening immediate family members of LS CRC patients (cascade testing) could provide a route to increase diagnoses of LS and improve prognoses through prevention, surveillance and treatment strategies. Cascade testing typically uses site specific germline testing to identify if family members have inherited the same variant as their relative. The NICE DG27 guidelines highlight the potential benefit to cascade testing, however, there are no explicit recommendations on how such genetic tests should be carried out. Objective: This evidence map will assess whether a more sustained review on screening for LS should be commissioned and evaluate the volume and type of evidence on key issues related to screening for LS. Given the available evidence and NICE guidelines on LS testing in CRC patients, this evidence map focuses on the evidence for testing asymptomatic relatives of CRC patients with LS. The map seeks to specifically address the following sub-questions: 1. Question 1: Are there any national or international guidelines or recommendations for targeted screening of LS in CRC patients and/or their asymptomatic relatives? 2. Question 2: What is the volume and type of evidence available on screening tests used to detect LS in asymptomatic relatives of CRC patients with LS mutations? 3. Question 3: What is the volume and type of evidence available on the penetrance of CRC among people who have mismatch repair gene mutations or EPCAM gene deletions? Methods: The evidence map will follow the UK NSC assessment framework. Systematic literature searches will be conducted in 2 databases (Medline and Embase) and 2 websites (Dimensions and TRIP). Records retrieved will be imported into EndNote, deduplicated, and screened by a single reviewer at title and abstract level. Full texts will not generally be assessed, but if a decision cannot be made from the title and abstract alone, and the number of publications is manageable, they will be reviewed. For Question 1, eligible studies must report any national and/or international guidelines/recommendations on targeted screening for Lynch syndrome in CRC patients and/or cascade testing of their asymptomatic relatives. For Question 2, eligible studies will compare germline testing with follow-up to CRC or any other genetic test in asymptomatic relatives of CRC patients with LS and report test accuracy measures. For question 3, eligible studies must report penetrance estimates of CRC in asymptomatic individuals with LS with confirmed MMR and EPCAM genetic variants. Conclusion: This evidence map will support UK NSC decision making on whether there is sufficient evidence to justify commissioning a more sustained review of the evidence on LS screening.
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