(22 March 2022) A novel screening service for Lynch syndrome, a condition that increases a person’s chance of certain cancers, which was developed by Newcastle Hospitals Trust and partners within the North East and Yorkshire Genomic Laboratory Hub (NE&Y GLH), is to be piloted by the Genomic Laboratory Hub network across England, following a funding award from the Small Business Research Initiative (SBRI) of £1.8 million.

Lynch syndrome is known to increase a person’s chances of developing certain types of cancer, particularly colon, rectal and uterine.

Implementation of this testing more widely should help early identification of thousands of cancer patients with Lynch syndrome across England and allow for more targeted treatment. It will also mean a test can be offered to relatives to see if they have the condition, in order to provide a programme of preventative care.

A recent survey by the National Disease Registration Service indicated that fewer than 1% of patients with a colorectal cancer receive testing for Lynch syndrome. This new approach to testing, initially developed by a Newcastle University research group, enables testing that is both quicker and available at a lower cost compared to traditional analysis.

The new test combines two stages of the testing pathway into a single test which also includes essential information about the types of mutation in the tumour, which will assist the patient’s Multi-disciplinary Team to recommend them more appropriate personalised treatments.

Ciaron McAnulty, Clinical Scientist at Newcastle Hospitals, said: “The success of creating this accessible test for Lynch syndrome is a strong example of close partnership working between NHS and research scientists, emphasising the value of sharing expertise and innovation across organisations.

“Bowel cancer is most often treatable and curable, especially if diagnosed early, with a good survival rate.”

“This test can be carried out at low cost and in high numbers. It will help to identify thousands of cancers earlier, when it is easier to treat, giving a much more positive outcome for patients and families.”

Professor Sir John Burn, Chair of Newcastle Hospitals Trust, said “28 years ago, we did the world’s first predictive test for Lynch Syndrome. Five years ago, NICE directed that all colorectal cancers should be tested for mismatch repair to help find people in need of testing, but very few complete the pathway. Our new MSI-plus assay can help fix that problem and help find the missing thousands.”

The national pilot is expected to begin in April 2022.

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Research overview

Colorectal cancers (CRCs) are the second highest cause of cancer death in England. Around 1 in 6 CRCs have Mismatch Repair (MMR) defects, and 1 in 5 of these develop in people with Lynch syndrome (LS) who have an inherited MMR defect. Having one pre-existing MMR defect in all cells makes total loss of MMR function in some cells much more likely. As MMR effectively spell-checks our DNA, total loss results in multiple mutations which can lead to cancer.

People with LS as young as 25 can get cancer in the bowel and other organs, and by age 65 more than two thirds will have had at least one cancer.

In 2017 NICE issued guidance that all colorectal cancers should undergo functional testing of the MMR genes to help identify potential carriers suitable for germline testing; this enables prospective surveillance, recommendation of regular aspirin as a cancer preventive agent and identification of asymptomatic relatives.

Traditionally, MMR defects are screened for in tumour samples by either Microsatellite Instability (MSI: a molecular fragment length analysis approach to identify the tell-tale DNA proof reading errors in highly repetitive regions) or immunohistochemistry (IHC: immunostaining for Lynch associated proteins). A second DNA test (BRAF) +/-MLH1 promoter methylation then excludes many non-inherited cases, before definitive testing for LS is offered.

A national review of testing in pathology departments and Genomic Laboratory Hubs in England in 2019 by the National Disease Registration Service has shown that the current pathway is not effective, with fewer than 1% of patients with a colorectal cancer undergoing germline testing for a Mismatch Repair gene pathogenic variant. An important cause for the failure of the pathway is the slow and iterative process of functional tumour testing.

In September 2020 the Newcastle Genetics Laboratory adopted a novel approach to MSI testing developed by a Newcastle University research group. The assay enables processing of up to 40 samples per run and includes simultaneous testing for BRAF, and other markers important for cancer treatment, at low cost. The analysis is also significantly streamlined given the binary output (stable / unstable) compared to the traditional fragment length analysis.

Colleagues from the NE&Y GLH in Newcastle and Sheffield undertook translational work to validate the assay in a diagnostic setting. This work was developed further with the creation of the MSI App, an online user interface reducing the analysis time even further. The MSI screening service is now available to patients in the North East.

In October the group was informed of its successful application to the Small Business Research Initiative Healthcare Cancer Programme with the proposal to implement this assay across all seven GLHs. The funding (£1.8 million) will allow all GLHs to assess the new assay in their work streams with an aim to replace fragment length analysis as the standard method of MSI testing.

The programme will start in April and the close working partnership between the NE&Y GLH and Newcastle University will continue through the training, development and implementation phases of the project.