New Study Enhances Detection of Mismatch Repair Deficiency in Endometrial Cancer

A pivotal study has evaluated the best approaches for detecting mismatch repair deficiency (MMRd) in endometrial cancer (EC), a crucial factor in diagnosing Lynch syndrome (LS) and determining patient suitability for immune checkpoint inhibitor (ICI) therapy. 

Every time our cells divide, they need to copy their DNA exactly. Occasionally, small errors slip into the sequence of DNA letters (A, T, C, and G), but our cells are equipped with a built-in proofreading system called DNA Mismatch Repair (MMR) to catch and fix these mistakes. When this system is faulty—a condition known as mismatch repair deficiency (MMRd)—errors go uncorrected, leading to a build-up of mutations. Over time, this can trigger the development of cancer. 

Lynch syndrome is a common inherited condition caused by faults in the MMR system. It affects around 1 in 300 people and significantly increases the risk of cancers, particularly colorectal and endometrial. Around 95% of those with Lynch syndrome don’t know they have it—meaning they miss out on life-saving early detection and prevention strategies. 

The good news is that cancers linked to MMRd, including those in people with Lynch syndrome, often respond exceptionally well to immunotherapy—a treatment that harnesses the body’s own immune system to fight cancer. Unlike chemotherapy or radiotherapy, immunotherapy tends to cause fewer and less severe side effects, offering a more targeted and tolerable option. This makes it all the more crucial to test cancers accurately, quickly, and affordably for MMR deficiency—not only to guide treatment, but also to identify individuals with Lynch syndrome. Once someone is diagnosed, their relatives can be offered genetic testing through a process called cascade testing. This allows more people to be diagnosed before they develop cancer, opening the door to prevention strategies that could stop cancer before it starts. 

Published in Cancers, the study compared three key methods for MMRd detection: immunohistochemistry (IHC), fragment length analysis (FLA), and a novel amplicon sequencing-based microsatellite instability (MSI) assay (NCL_MSI).  

The findings provide essential insights that could improve diagnostic accuracy and treatment pathways for thousands of patients. 

These findings have significant clinical implications for NHS diagnostic protocols and global cancer care. The study confirms that IHC remains the most reliable first-line test for MMRd and Lynch syndrome detection, while the NCL_MSI assay provides an additional, highly accurate method for confirming cases with inconclusive results. This is important as IHC is widely available and cheap.  

By refining MMRd detection, this research paves the way for more precise immunotherapy selection, reducing unnecessary toxicity and ensuring patients receive the most effective treatment. These findings could directly improve patient outcomes and optimise NHS resources, marking a significant step forward in personalised cancer care. 

This research was a collaboration between Newcastle University, Newcastle Hospitals NHS Foundation Trust, Ohio State University, The University of Manchester, Manchester University NHS Foundation Trust, and The University of Edinburgh. 

Neil Ryan is a trainee in Gynaecology Oncology at the Royal Infirmary of Edinburgh and a Clinical Lecturer at the University of Edinburgh.  

Neil has been invited to sit on several national and international committees including the Royal College of Obstetricians and Gynaecologists (RCOG) Genetics Task Force, The British Gynaecological Cancers Society's guideline subcommittee, The European Hereditary Cancer Group, Lynch Syndrome UK's Clinical Advisory group and the Royal Society of Medicine's Obstetrics and Gynaecological committee.   

Neil is seeking to explore ways to improve the care of women with gynaecological cancer by improving personalised treatments and identifying those at increased risk of cancer.