Urine DNA testing as a non-invasive screen for urothelial cancer in people with Lynch syndrome

Plain English summary of protocol

Background and study aims
Urothelial cancer is a tumour of the lining of the urinary tract, which includes parts of the kidneys, the ureters, the bladder, and the urethra. People who have Lynch syndrome have up to a 1-in-4 chance of developing urothelial cancer during their lifetime, making it the second or third most common Lynch syndrome cancer. However, there are no suitable surveillance or prevention options.
This study will use a DNA-based test to screen for urothelial cancer DNA in urine samples. Collection of urine is easy and painless and can be done at home with postage of the urine sample to the laboratory. A pilot study has shown that the urine test (the Newcastle MSI-Plus Assay) could be a highly accurate test for urothelial cancer. However, the pilot study included only a few hundred people and so these accuracy estimates are uncertain. We also do not know how well the test detects early-stage tumours and need quality of life and cost data to understand the health economics of offering a urine surveillance programme to people with Lynch syndrome.

Who can participate?
People aged 40 years or older who have a diagnosis of Lynch syndrome caused by the MLH1, MSH2, or MSH6 gene can take part. This study will primarily recruit people with MSH2-Lynch syndrome as they are at highest risk of developing urothelial cancer.

What does the study involve?
Potential participants will be contacted by participant identification centres across NHS England, NHS Scotland, and NHS Wales. Potential participants will be sent a study advert, including a brief summary of MUSICaL and contact details for the research team at Newcastle University / Newcastle upon Tyne Hospitals NHS Foundation Trust to be able to get more information and be recruited.
When a potential participant contacts the research team, they will be screened for eligibility and then provided with the participant information sheet and consent form by email if eligible and willing to take part. Once the consent form has been completed, the participant will be sent a short electronic questionnaire to collect personal details needed for contact and sample collection, as well as important health data. If a (potential) participant can’t use email, a member of the research team will send information about the study and consent form by post and can complete questionnaires on their behalf via telephone.
Participants will be sent a sample collection kit to their home address within a few months of consenting to the study. This may be a few months to ensure capacity in the laboratory to process the sample. This kit contains a device called a ColliPee to collect the urine sample. The kit will include clear instructions to follow. There will be a label for time and date of sample collection. The sample will be sent by the participant to the research team via the post using the pre-paid and addressed postage box that is included with the kit. Sample collection is easy and all costs are covered. There will also be two short questionnaires sent by email for the participant to complete on symptoms and quality of life at the time of sample collection. These questionnaires will each take less than 5 minutes to complete. If a participant is unable to use email, a member of the research team can complete questionnaires on their behalf via telephone.
The urine test result will be sent to participants in 2 months or less of sample collection. Participants will be informed at the time what to do next.
About 2% of urine tests are expected to give a positive result. Participants with a “positive” result (the urine has MSI) will be sent a new sample collection kit and asked to send a second urine sample to confirm the result. If the second sample is also positive, the MUSICaL clinical team will refer the participant to their local hospital for further investigations for urothelial cancer. The urology clinic will likely involve the following, though investigations may vary:
1. CT urogram, a non-invasive imaging test that combines X-rays and computers to create highly detailed, 3D cross-sectional images of the kidneys, ureters, and bladder.
2. Cystoscopy, a minimally invasive test using a camera on a thin tube inserted through the urethra (the tube connecting your bladder to the outside) to view the inside of the urethra and bladder and the openings of the ureters.
If the participant has a womb, they may also be referred to a gynaecology clinic as a womb cancer could cause the positive result. The gynaecology clinic will involve the following, though investigations may vary:
3. Trans vaginal ultrasound scan, a non-invasive imaging test that uses ultrasound to assess the inside of the womb.
4. Hysteroscopy, a minimally invasive test using a camera on a thin tube inserted through the vagina and cervix to examine the inside of the womb. A biopsy (small tissue sample) of the womb lining will likely be taken.
About 98% of urine tests are expected to give a negative result. If a participant’s urine test result is “negative” (the urine does not have MSI), they will not need any further tests or investigations but will be followed for at least 2 years by the research team to see if they develop urothelial cancer despite the negative result.
Rarely, the first urine test will be positive but then the confirmatory test will be negative. This probably means the first result was a “false positive”. In some cases, this could be a small tumour or precancerous lesion that has been destroyed by the immune system. To make sure, another urine test kit can be sent approximately 12 months later.
Regardless of test result, if a participant is found to have a cancer, the research team will establish regular contact with their local clinical team and will send additional urine sample collection kits to their home at key timepoints during treatment (for example before and after surgery). These additional samples will allow changes in the urine MSI signal to be tracked. Details of the cancer, including its stage and grade, and tumour tissue will be requested from the hospital responsible for treatment. A blood sample may also be collected during treatment appointments. Tumour and blood samples will allow us to confirm that the urine MSI signal originates from the cancer when the urine test is positive, or investigate why the cancer was missed when the urine test is negative. The blood sample is helpful for this analysis but is not needed, so the participant can choose not to give a blood sample.
In some cases, the research team will also access tumour tissue and data from cancer diagnoses that occurred before a participant started on the study. For example, the urine test may detect recurrence of a cancer that was treated before starting on the study, in which case the pre-study cancer will need to be analysed to see if the tumour MSI signal matches the MSI signal in the urine.
During follow-up, participants will be asked to complete a short electronic questionnaire sent by email every 6 months after the initial urine sample to inform the research team if they have had a cancer diagnosis or symptoms since last contact. There will also be a short electronic questionnaire on health-related quality of life that uses simple scoring systems. These questionnaires will each take less than 5 minutes to complete. On rare occasion, the research team may also contact participants by telephone. If a participant is unable to use email, a member of the research team can complete questionnaires on their behalf via telephone.

What are the possible benefits and risks of participating?
Participants will be contributing to research that may benefit the wider Lynch syndrome community. Although this testing approach needs to be carefully evaluated, participants could benefit from early detection of a cancer that is not showing any symptoms, which may be curable without needing an operation. Urine samples will also be tested after treatment for cancer, which can detect regrowth of the cancer and allow the clinical team to adapt their treatment plan. Participants will have the support of the expert clinical team leading the study, who have decades of experience caring for and running clinical trials for people with Lynch syndrome.
There are minimal risks to participating. The ColliPee device for urine sample collection is safe and easy to use. The data analysis and urine sample testing will be carried out by expert scientists at Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust. The test has quality control metrics to ensure a reliable result. The test was highly accurate during a pilot study, giving a “positive” result in 100% of urothelial cancer patients and giving a “negative” result in 99.5% of people without urothelial cancer. However, these results are based on small numbers and the true accuracy of the test may vary. There is a risk of incorrect test results:
1. “False positive” results, meaning the test indicates a cancer may be present when there is no cancer, can lead to unnecessary anxiety and further clinical investigations.
2. “False negative” results, meaning the test indicates there is no cancer when a cancer is present, can lead to false reassurance. Participants will be advised of symptoms to be aware of regardless of the test result.
There will be additional clinical investigations in a urology or gynaecology clinic after a positive test result, which will occur in about 2% of participants. These are generally safe and are standard clinical procedures when cancer is suspected but do carry some risks. Participants will be informed of these risks in detail in preparation for the clinic.
Screening for cancer can sometimes detect very slow growing tumours that do not cause ill health and so would not have impacted day-to-day life or lifespan if undetected. This is known as over-diagnosis. Therefore, screening for urothelial cancer in this study may lead to over-diagnosis and unnecessary investigations and treatment.

Where is the study run from?
Newcastle upon Tyne Hospitals NHS Foundation Trust (UK)

When is the study starting and how long is it expected to run for?
November 2026 to October 2029

Who is funding the study?
Cancer Research UK

Who is the main contact?
Dr Richard Gallon, richard.gallon@newcastle.ac.uk

Contact information

Dr Richard Gallon
Principal investigator, Scientific, Public

Newcastle University, International Centre for Life, Central Parkway
Newcastle upon Tyne
NE1 3BZ
United Kingdom

ORCID ID	0000-0002-5395-0099
Phone	+44 (0)7530949298
Email	richard.gallon@newcastle.ac.uk

Study information

Eligibility

Locations

Countries of recruitment

• United Kingdom
• England
• Scotland
• Wales

Study participating centres

Results and Publications

Editorial Notes

27/10/2026: Study's existence confirmed by the NIHR.