Communications and Marketing

Computer Model to Predict Prostate Cancer Progression

No. 68 | 11/12/2018

An international team of cancer researchers from Germany and Denmark have used cancer patient data to develop a computer model that can predict the course of disease for prostate cancer. The model is currently being implemented at a prostate cancer clinic in Germany. The researchers have also found the enzyme that appears to trigger some of the first mutations in prostate cancer.

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Prostate cancer is one of the most frequently diagnosed cancer in men in the western world with more than a million new cases each year. One of the key challenges is to differentiate between aggressive and non-aggressive disease. An international team involving researchers from BRIC at the Faculty of Health and Medical Sciences, the University of Copenhagen, and Rigshospitalet, the German Cancer Research Center (DKFZ) and the European Molecular Biology Laboratory (EMBL) in Heidelberg will solve this challenge with a computer model.

The researchers have studied the earliest mutational events in prostate cancer to develop a computer model, described in a new study that has just been published in the scientific journal Cancer Cell. The researchers collected patient data from close to 300 men who have had their entire cancer genome sequenced to characterise all mutations present in the tumour. Based on the data set, the researchers have developed the computer model which can be used to predict how prostate cancer will develop for a given patient.

'If we have a patient with a particular set of mutations, we can use the model to predict the most likely next mutation that the patient will experience at some point - and how it will affect the patient's clinical situation. As an illustration, we can predict with some probability that if you have mutation A, you are likely to get mutation B before you get C. We can also predict if the next mutation is likely to change the clinical outcome of the disease'.

'So far, our data sets comprise around 300 patients, but we expect to collect data from several thousand patients in the coming years. The model will be better the more data it can learn from', says group leader and co-author of the study Joachim Weischenfeldt, BRIC, UCPH.

The computer model is currently being implemented at a clinic in Germany. The researchers expect it to take two to three years to have the model fully implemented as an integral part of the clinic's processes. Later, in a not too distant future the researchers hope that the model can also be introduced at hospitals in other countries, for example Denmark.

Mechanism Contributing to the First Mutations in Prostate Cancer Have Been Found

The approximately 300 patients from the study all had their entire genome sequenced. With genome sequencing, it becomes possible to tailor the treatment of the individual - also referred to as personalised medicine. The patients whose data the researchers have used have primarily been so-called early onset patients. This group is defined as men who are diagnosed with prostate cancer before reaching the age of 55 years.

'Prostate cancer develops over many years. We have therefore been particularly interested in the group of patients where the cancer is detected at young age as this allows us to analyse the tumour at an early stage. This is an important element because in this way we get a cleaner picture of the first mutations and alterations that occur in the tumour, to find out what is the initiating factor', says co-author Doctor Clarissa Gerhauser, DKFZ.

So far, it has not been known precisely what initiates prostate cancer. However due to the focus on the earliest detected tumours, the researchers uncovered a mutational mechanism involving an enzyme called APOBEC. This enzyme may help trigger the disease – i.e. trigger some of the very first mutations in prostate cancer.

'We hypothesise that this enzyme mutates the prostate cells at a low but constant rate. Each time the cell divides, APOBEC is likely to cause mutations. If you have early-onset prostate cancer, you may have a couple of mutations caused by APOBEC. Twenty years later, you may have 10-20 mutations', says co-author Doctor Jan O. Korbel, group leader at EMBL.

'The most common oncogene in prostate cancer involves a certain fusion gene. The APOBEC enzyme may contribute to the formation of this fusion gene. We cannot say that there is causality, but there is a strong correlation between mutations caused by APOBEC and other alterations such as this fusion gene,' says Joachim Weischenfeldt.

The researchers have also found a putative novel oncogene in prostate cancer – ESRP1 – which is associated with very fast-dividing and highly aggressive prostate cancer. It is located closely to an already known oncogene, and the researchers believe this is the reason that it has not been discovered until now. In the study, the researchers show that the oncogene ESRP1 may be used as a possible new biomarker to detect whether a patient will have aggressive prostate cancer, which they validated on a cohort consisting of 12,000 other patients with the same type of cancer.

The study is the result of a large transnational collaboration between universities from different countries among others Germany, Norway, Canada and Denmark. Besides UCPH, DKFZ, EMBL, Max Planck Institute for Molecular Genetics and Charité – Universitätsmedizin Berlin has e.g. also been involved with professor and co-author Thorsten Schlomm, who is leading the clinical implementation of the computer model at the clinic in Germany.

The study is supported by the German Federal Ministry of Education and Research (BMBF) through projects for early onset prostate cancer, the Arvid Nilsson Foundation, Rigshospitalet's Research Foundation, the ERC Starting Grant, the Sander Foundation, grant from the Helmholtz International Graduate School at the German Cancer Research Center, the Norwegian Research Council and the American National Institute of Health.

C. Gerhäuser et al.: Molecular Evolution of early onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 2018, DOI: 10.1016/j.ccell.2018.10.016

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

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