Analysis of Lynch Syndrome Diagnostic Pathway

Introduction

Lynch Syndrome (LS) is a hereditary cancer susceptibility syndrome that primarily leads to the occurrence of colorectal cancer (CRC), endometrial cancer, and several other types of cancer. Although the incidence of Lynch Syndrome among cancer patients and its importance to public health have been gradually recognized, its actual diagnosis rate is extremely low, with estimates suggesting that over 95% of Lynch Syndrome patients remain undiagnosed. However, in 2017, the UK National Health Service (NHS) issued new guidelines recommending that all colorectal cancer cases should undergo DNA mismatch repair deficiency (dMMR) testing to better identify these patients and improve their prognosis.

Research Background

This study was conducted by a research team including Fiona E. McRonald, Joanna Pethick, Francesco Santaniello, and others, affiliated with institutions such as the National Disease Registration Service (NCRAS) of England and Guy’s and St. Thomas’ NHS Foundation Trust. The research findings were published in the European Journal of Human Genetics in 2024. The study utilized a nationwide dataset from NCRAS to evaluate the implementation of the diagnostic guidelines issued in 2017 in actual practice.

Research Methods

The study data covered all colorectal cancer cases diagnosed in England in 2019. Through retrospective analysis, the research team collected and compiled data on 37,662 colorectal tumors, including patient demographics, tumor information, and laboratory diagnostic data for dMMR.

Specifically, the data analysis included: 1. Cancer registration data: A population-based cancer registry database created by NCRAS. 2. Somatic genomic testing data: Obtained through customized data summaries provided by individual genetic laboratories and through the nationally mandated Cancer Outcomes and Services Dataset (COSD). 3. Germline data: MMR gene data processed through pseudonymization and bioinformatics pipelines.

Additionally, the research team conducted descriptive statistical analysis, chi-square tests, t-tests, and regression analysis to examine the correlation between demographic variables and dMMR test results and follow-ups.

Key Findings

1. Somatic testing:

   • Of the 37,662 colorectal cancer tumors diagnosed in 2019, only 44% received dMMR testing.
   • IHC (immunohistochemistry) was the most common testing method, accounting for 89%, while MSI (microsatellite instability) testing accounted for 8%.
   • 16% of tumors showed dMMR, of which 85% had MLH1 protein deficiency, but only 54% subsequently received further somatic testing.

2. Disparities in follow-up testing:

   • Significant regional differences in dMMR testing rates, with more than a fourfold difference between the highest and lowest regions.
   • Follow-up testing (somatic or germline testing) also showed significant regional differences, and the implementation rates of somatic and germline testing following dMMR testing were insufficient.

3. Germline testing:

   • Overall, only 1.3% of colorectal cancer patients received germline MMR gene testing.
   • According to the national genetic testing directory standards, 507 patients were eligible for germline testing in 2019, but only 180 patients (36%) actually underwent germline MMR gene testing.

Conclusions and Significance

Through detailed analysis of the testing pathway for colorectal cancer patients in England in 2019, the study drew the following main conclusions:

1. Low testing rates and underdiagnosis: Despite NICE (National Institute for Health and Care Excellence) guidelines clearly requiring testing of all colorectal cancer patients, the actual testing rate was below 50%, showing significant regional inequalities. This low testing rate further supports the view that Lynch Syndrome is severely underdiagnosed.

2. Time delay issues: There were long time delays throughout the pathway from initial diagnosis to functional MMR testing, further somatic testing, and germline testing, limiting the efficiency of diagnosis and timeliness of follow-ups.

3. Need for strengthened policy implementation: The study shows that if NICE diagnostic guidelines were fully implemented, approximately 700 new Lynch Syndrome cases could be identified annually, significantly improving patient survival rates and reducing medical costs.

4. Importance of national data collection: This study demonstrates the necessity and prospects of linking nationwide cancer records with molecular testing data (including somatic and germline data), providing a powerful reference for future diagnostic improvements.

This study not only reveals the current status and challenges of the Lynch Syndrome diagnostic pathway implementation in England but also provides important baseline data for future improvements and policy implementation. Through continuous data monitoring and analysis, we can promote the development of tumor diagnostic technologies on a larger scale and improve overall public health levels.