Tumor Genetics Blog

By: Lauri Ryyppö

Science comes in many forms, and there is a lot to do regarding scientific publications. When thinking about scientists, one might first think about the archetype examples, such as Marie Curie, Charles Darwin, or even Sheldon Cooper conducting their experiments or pondering the essence of life. Science has loads of different dimensions to improve upon. The applications, for example, in sequencing technologies, might make a dent in how healthcare is conducted.

What do we need?

In the modern world, we can be connected instantly, and we can have all the information in the world in the palm of our hands. Yet, in biomedical research, connection and information alone are not enough. We also need patient samples. One sample from one patient is easy to acquire. Still, the workload increases significantly if more than one sample is needed and a more complex operation is required to diagnose the patient. Quickly we realize that the equation is quite challenging to fulfill in the long term and for large masses of people.

In our study, the patient usually arrives at the clinic because they have detected blood in their urine, referred to as haematuria. To rule out urothelial cancers, they must undergo a cystoscopy, where a medical professional visually investigates the bladder’s lining. Only about 10% of patients with haematuria are diagnosed with cancer. But patients diagnosed with cancer must undergo residual disease testing after their first-line treatment. Currently, residual disease testing is also based on cystoscopies.

Performing cystoscopies for diagnoses and residual disease testing is resource heavy as only a tiny part of these cystoscopies finds anything that causes concern. Therefore, we have started a trial where the aim is to replace the majority of cystoscopies with a DNA urine test.

What is investigated?

In the urine sample we collect, we are trying to find if the person has any aberrations in their DNA. The aberrations are searched for by leveraging sequencing technologies. In sequencing, the sequence’s four bases are read: A adenine, T thymine, C cytosine, and G guanine. The DNA sequence can be thought of as the instructions for building us. Sometimes, especially in cancers, the instructions can be damaged, or they can become unreadable.

Catching these damaged sequences is a way to catch cancer! If a person is cancer positive based on the urine DNA test, they are then further analyzed to confirm and to find the extent of the possible cancerous tumor. Still, if a DNA test could replace 90% of the cystoscopies in the diagnosis phase, then the financial burden placed on healthcare by the cystoscopies would decrease significantly.

When visually inspecting the bladder’s lining during a cystoscopy, some urothelial cancer types might be missed, meaning the present solution is not 100 % sensitive. Some tumors are more challenging to catch than others. For example, if the patient has an infection ongoing in the bladder during the cystoscopy, the cancerous tissue might be missed. Also, some bladder cancers grow as sheets of epithelial cells, referred to as carcinoma in situ (CIS). The CIS cases mask themselves effectively, causing the operation to sometimes be futile in catching cancer.

How to do it?

When investigating the urine DNA, the sample is sent to us as a post package. There are a few kinks to iron out for this sort of sample collection to work. First, the DNA in the urine must endure until it can be processed in the laboratory. We are tackling this by having the patient add a Streck preservative into the urine. Secondly, the patient’s urine samples can contain DNA of different origins. Part of the DNA can be in the supernatant, but DNA may also be found inside the cells in the urine. Factors such as age, medical conditions, and liquid intake can drastically affect the yield of DNA that we can extract.

When basing the diagnoses and residual disease testing on a DNA test, the information gained from sequencing patient samples can afford some added value. For example, the patient’s treatment can be targeted based on the genomic profile. For instance, FGFR inhibitors can be effectively used in cases with a specific tumor subtype.

What is this used for?

Our system is in use to collect urine samples at TAYS, the Tampere University Hospital. The study has so far been successful in accomplishing 97% sensitivity for pre-operative bladder cancer cases. In detecting the rarer urothelial tract cancers UTUCs (Upper Tract Urothelial Carcinoma), we have had a sensitivity of 84%. In addition, we have successfully recognized all CIS cases that are hard to catch using traditional methods.

In addition to these endeavors, we send urine collection boxes to patients in the Lynch syndrome registry in Finland (LSRFi registry). People with Lynch syndrome have a mismatch repair (MMR) system mutation, and patients with an MSH2 mutation are more likely to develop urothelial cancer. We aim to screen this population with our urine DNA test.

In the future, we hope that urine DNA tests can be used as a standard step in diagnosing patients with urothelial cancer. The cystoscopies used in post-operative settings could also be replaced with urine DNA tests. These goals would make life easier and more comfortable for the patients while simultaneously decreasing the costs of public healthcare.

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