Lynch Syndrome, Urothelial Carcinoma
Conditions
Keywords
Lynch syndrome, Hereditary cancer syndrome, Screening, Urothelial neoplasms, Bladder neoplasms, Upper tract urothelial neoplasms, Urogenital diseases, Liquid biopsies, Urine tumor DNA
Brief summary
Lynch syndrome (LS) is an inherited cancer predisposition syndrome caused by pathogenic germline variants in DNA mismatch repair (MMR) genes. New cancer screening and diagnostic tools are urgently needed to identify LS-related cancers early enough for curative treatment. Urothelial cancers (comprising bladder and upper tract urothelial tumors) are the third most common cancer after colorectal and endometrial cancers in individuals with LS. Up to one in four LS individuals will develop urothelial cancer during their lifetime, with the risk varying based on the defective MMR gene. In this clinical trial, we will employ urine tumor DNA (utDNA) to identify asymptomatic urothelial cancers in Lynch syndrome patients, and to investigate the potential benefits of urine tumor DNA based screening in this high-risk population.
Interventions
DIAGNOSTIC_TESTUrothelial cancer screening using urine tumor DNA test
Urine sample DNA is analyzed using a targeted sequencing panel encompassing the coding regions of 21 genes that are recurrently mutated in urothelial cancer
DIAGNOSTIC_TESTUrothelial cancer screening using urine cytology (comparator)
Urine cytology sample
Sponsors
Tampere University
Tampere University Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
SCREENING
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Willing and able to provide informed consent * Diagnosis of Lynch syndrome * Age 50 - 75 years at study recruitment
Exclusion criteria
* Concurrent urothelial carcinoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity and specificity of positive utDNA for urothelial cancer within one year of follow-up | At 1 years of follow-up | Sensitivity and specificity of positive utDNA for urothelial cancer, using histologically verified cancers detected within 1 year of the utDNA test as ground truth |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Urothelial cancer specific survival | At 3, 5 and 10 years of follow-up | Urothelial cancer specific survival survival in utDNA positive and negative patients |
| Time to diagnosis of urothelial cancer | At 2, 5 and 10 years of follow-up | Time to diagnosis of urothelial cancer in utDNA positive and negative patients |
| TNM pathological stage of urothelial cancers | At 2, 5 and 10 years of follow-up | TNM pathological stage (American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC)) of urothelial cancers found in utDNA positive and negative patients |
| Size of urothelial tumors | At 2, 5 and 10 years of follow-up | Maximum diameter of urothelial tumors found in utDNA positive and negative patients |
| Urothelial cancer grade | At 2, 5 and 10 years of follow-up | The World Health Organization (WHO) 2004/2016 grading of urothelial cancers found in utDNA positive and negative patients |
| Specificity of positive utDNA for urothelial cancer at the time of testing | After all patients with positive utDNA have been evaluated with cystoscopy and/or imaging | Specificity of positive utDNA test for urothelial cancer, using histologically verified cancers detected in the cystoscopy and/or imaging performed due to positive utDNA test as the ground truth |
| Sensitivity and specificity of positive utDNA for urothelial cancer within multiple years of follow-up | At 2, 5, and 10 years of follow-up | Sensitivity and specificity of positive utDNA for urothelial cancer, using histologically verified cancers detected within 2, 5, and 10 years of the utDNA test as ground truth |
| Overall survival | At 5 and 10 years of follow-up | Overall survival in utDNA positive and negative patients |
| Time to metastatic urothelial cancer | At 5 and 10 years of follow-up | Time to metastatic urothelial cancer in utDNA positive and negative patients |
| Time to diagnosis of muscle invasive or high grade urothelial cancer | At 2, 5 and 10 years of follow-up | Time to diagnosis of muscle invasive or high grade urothelial cancer in utDNA positive and negative patients |
Other
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of somatic second hit in MMR genes | At 1, 2, 5 and 10 years of follow-up | Prevalence of somatic second hit and additional somatic hits in mismatch repair genes (MSH2, MSH6, MLH1, PMS2) in Lynch syndrome patients diagnosed with urothelial cancer |
| Cost of utDNA screening | At 1, 2, 5 and 10 years of follow-up | Analysis of the cost of utDNA screening, including cost per urothelial cancer found |
| Association of utDNA fraction with time to diagnosis of urothelial cancer | At 2, 5 and 10 years of follow-up | Association of utDNA fraction (quantified based on mutation allele fractions in urine DNA) with time to diagnosis of urothelial cancer |
| Sensitivity and specificity of urine cytology | At 1 year of follow-up | Sensitivity and specificity of urine cytology for detecting urothelial cancer, using histologically verified cancers detected within 1 year of cytology as ground truth |
Countries
Canada, Finland
Contacts
Primary ContactJussi Nikkola, MD, PhD
Outcome results
None listed