A diagnosis of bile duct cancer means almost certain death, because it is resistant to known treatments but especially because it is often detected so late that it cannot be treated. Comprehensive analysis of genetic markers among people with and without bile duct cancer has led researchers to seven blood biomarkers that can potentially be used to detect the disease. This finding may lead to this type of cancer being diagnosed earlier in the future so that it can be treated more easily and perhaps even eventually cured.
Cancer is one of the most feared diseases, especially because of how it often strikes suddenly and dramatically. However, although the ability to cure many types of cancer is increasing significantly, some types remain unsolved riddles that relentlessly take apparently healthy people’s lives prematurely. Bile duct cancer (cholangiocarcinoma) is one such type, and an intense research effort is therefore underway to understand and specifically detect it.
“Early diagnosis is vital for effectively treating bile duct cancer, and a key challenge is the ability to detect it without having to resort to tissue biopsy. In our new study, we succeeded in finding seven blood-based biomarkers that can apparently distinguish between people with and without bile duct cancer. Based on these findings, we are now launching a major prospective trial to determine which of these indicators are most accurate, and which can be incorporated into standard testing in hospitals,” explains Jesper Bøje Andersen, Associate Professor and group leader at the Biotech Research and Innovation Centre (BRIC), University of Copenhagen.
A profile of cancer cells
Although bile duct cancer is relatively rare in Denmark, with only a few hundred new cases per year, the prevalence has increased rapidly in recent decades, probably in association with the growth in the numbers of people with obesity and people with diabetes, both of which may be risk factors. A major international research collaboration has succeeded in shedding new light on this very rare and deadly type of cancer.
“The purpose of our study was to try to develop a new way to detect bile duct cancer. The only diagnostic method has been to biopsy the tumour site, but this is an expensive, difficult and invasive method. We therefore tried to find biomarkers in blood and urine that could detect the disease more easily and non-invasively,” says Jesper Bøje Andersen.
The researchers focused on extracellular vesicles – tiny transport particles released by both healthy and cancer cells and present in blood and urine. By examining the content of the vesicles, the researchers can construct a profile of the body’s cells. In this project, the researchers investigated the profile of the messenger RNA (mRNA) molecules.
“This enabled us to determine which genes – DNA – have been transcribed into RNA, and this then comprises the template for creating proteins. And some RNA molecules were overexpressed among people with cancer compared with healthy people. We discovered five candidates in blood and two in urine, which may comprise future biomarkers for differentiating people with bile duct cancer from healthy people,” explains Jesper Bøje Andersen.
Major European collaboration
According to Jesper Bøje Andersen, the results are promising for many reasons. First, the mRNA copies were not simply copies of random genes but could be traced back to the cancerous tissue. In addition, many of the biomarkers are already known to be associated with cancer, including c-Maf-inducing protein (CMIP).
“CMIP has been shown to influence the development of gastric cancer, so although we do not fully know the mechanism in bile duct cancer, CMIP is a very promising biomarker, and perhaps can eventually be studied as a therapeutic target,” says Jesper Bøje Andersen.
Finding new diagnostic tools is part of a major long-term European collaboration. This time Jesper Bøje Andersen’s close collaborator, Jesus M. Banales, Donostia University Hospital, San Sebastian, Spain, led the project, but the researchers help each other and share the important data in their quest to better understand, detect and potentially cure bile duct cancer.
“We have established a close collaboration in Europe on bile duct cancer and are both co-founders of the European Network for the Study of Cholangiocarcinoma (http://www.enscca.org), which today includes research groups from 12 countries,” says Jesper Bøje Andersen.
“One major problem is that surgery is the only treatment and can only be offered to 10–30% of the patients diagnosed with bile duct cancer. It is also resistant to chemotherapy, and the cause is largely unknown. Both environmental and hereditary factors seem to play a major role, and we can see that people with inflammation of the bile ducts – such as primary sclerosing cholangitis – and chronic liver inflammation are especially susceptible, but there is still a long way to go to understand the molecular pathogenesis of bile duct cancer,” says Jesper Bøje Andersen.
Requires diagnostic accuracy
To understand the high-risk groups more fully, the researchers in this international collaboration are investigating predisposing factors through a registry that includes more than 3000 people. A research group at the Mayo Clinic in Rochester, Minnesota is leading this genetic study, which includes blood samples from more than 1000 people in Europe, including about 500 from Herlev and Gentofte Hospital. If these factors can be found, the new diagnostic results may become even more useful.
“Today, bile duct cancer is diagnosed so late that it often has progressed locally or even metastasized. The disease usually appears as an obstruction in the bile ducts – cholestasis – that results in altered bile flow and causes jaundice or itching, but when this happens it is usually too late. Regularly screening high-risk groups with new and easier methods may therefore be an important step in initiating early treatment,” explains Jesper Bøje Andersen.
First, the researchers must validate the new results in a large international cohort to determine which of the seven possible biomarkers to pursue and whether they have sufficient diagnostic accuracy.
“Then comes the major work of translating our results to clinical settings. We need to develop a technique that can be easily implemented and especially approved for use in hospitals and by doctors. We will try to use existing and approved techniques, and this may speed up the process. If all goes well, a new non-invasive test may be ready within 5 years. The outlook is promising, although this is a very optimistic time frame,” concludes Jesper Bøje Andersen.
“Patients with cholangiocarcinoma present specific RNA profiles in serum and urine extracellular vesicles mirroring the tumor expression: novel liquid biopsy biomarkers for disease diagnosis” has been published in Cells. The Novo Nordisk Foundation awarded Jesper Bøje Andersen grants for the projects: A Role for Aberrant miRs in Inherited Drug Resistance: Tumor Heterogeneity and Novel Compensatory Pro-tumorigenic Mechanisms in Liver Cancer (2015) and Characterization of Lysine Demethylase (KDM)-inhibitor Sensitive Bile Duct Cancer in the Liver (2019).