Researchers examined if genetic differences in bladder cancer patients play a key role in the course of the disease

To determine if genetic differences in bladder cancer patients affect the severity and chance of non-muscle-invasive bladder cancer relapsing, a group of researchers performed the largest genome-wide association study (GWAS) to date. The research was led by postdoc Jasper Hof from Center for Quantitative Genetics and Genomics (QGG). Even though the study found no strong genetic markers that could predict the behavior of bladder cancer, the researchers identified 16 genes that potentially play a key role and therefore warrants further research. Additionally, the study identified 2 specific genes that might influence the chance of relapse for bladder cancer patients treated with Bacillus Calmette-Guérin (BCG). 

Jasper Hof emphasizes the importance of continued research on this area: 

‘- Patients with bladder cancer are severely burdened by long follow-up in the hospital to check whether the cancer has recurred. This could be significantly improved if we knew who is most likely to develop this recurrence, and who is not.’

There are two types of bladder cancer: non-muscle-invasive bladder cancer and muscle-invasive bladder cancer. While the non-muscle-invasive type of bladder cancer is less severe and fatal than the muscle-invasive type, it tends to relapse or progress into a more severe case after treatment. The problem is that it is very hard to predict when and why the cancer acts this way. It is already known that the size of the tumors, the amount of tumors, whether the patient has had a relapse before and the progress of the cancer are factors that all play a role in the progression and relapse. What makes it hard to predict is that two patients with nearly identical tumors often have two very different disease courses.

Therefore, researchers examined if the genetic differences in the patients play a key role in the course of disease. To examine this, the researchers performed a Genome-Wide Association Study. The study included 5,009 patients from The Netherlands, Canada, Britain and Spain, each measured for their DNA. More than 4,200 cases of relapse were reported, and 742 cases of cancer progression were reported, making it the largest GWAS performed to date.

The researchers did not find any certain genetic variants that could predict the course of disease, which likely points to the fact that the course of disease is not dictated by specific genetic variants. But even though they did not find specific genetic variants that can predict a course of disease, they identified 2 genetic variants that possibly influence the chances of the cancer relapsing. This is not a certainty though and therefore warrants further research. The researchers note that this uncertainty stems from the study having few patients in this specific group of genetic variants and the results varying between the patients.

Additionally, the study identified 101 candidate genes, where 16 of these may play a role in the course of disease. Some of these genes have earlier been identified as having a connection to bladder cancer, strengthening the plausibility of a role in bladder cancer relapse.

‘- These results of our study can help to identify biomarkers to predict those individuals at highest risk of recurrence and ultimately support personalized medicine.’ says research leader Jasper Hof.

For further information, please contact Postdoc Jasper Hof, Center for Quantitative Genetics and Genomics.

Additional information
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Study type	GWAS study
Funding	The University of Sheffield collection was partly funded by Yorkshire Cancer Research (program grant number S305PA: Genetic instability and death in cancer cells). James W.F. Catto is funded by an NIHR research professorship. Sita H. Vermeulen was supported by a grant from the Netherlands Organization for Scientific Research (NWO Vidi 91717334). The University of Birmingham collection was funded by Cancer Research UK (C1343/A5738), the University of Birmingham, and the Birmingham and The Black Country and West Midlands North and South Comprehensive Local Research Networks, UK. The UroLife study was financially supported by Alpe d’HuZes/Dutch Cancer Society (KUN 2013-5926) and Dutch Cancer Society (2017-2/11179). This work used the Dutch national e-infrastructure with support of the SURF Cooperative using grant no. EINF-12128.
Collaborators	Jasper P. Hof: Writing – review & editing, Writing – original draft, Data curation, Investigation, Formal analysis. Tessel E. Galesloot: Writing – review & editing, Writing – original draft, Data curation, Investigation, Formal analysis, Conceptualization. Katja K.H. Aben: Writing – review & editing, Resources. Richard T. Bryan: Writing – review & editing, Resources. James W.F. Catto: Writing – review & editing, Resources. Kar K. Cheng: Writing – review & editing, Resources. Samantha Conroy: Writing – review & editing, Resources. Neil E. Fleshner: Writing – review & editing, Resources. Antoine G. van der Heijden: Writing – review & editing. Nicholas D. James: Writing – review & editing, Resources. Lourdes Mengual: Writing – review & editing, Resources. Florine M. Uunk: Writing – review & editing. Gerald Verhaegh: Writing – review & editing, Resources. Alina Vrieling: Writing – review & editing, Resources. Maurice P. Zeegers: Writing – review & editing, Resources. Lambertus A.L.M. Kiemeney: Writing – review & editing, Resources, Conceptualization, Supervision. Sita H. Vermeulen: Writing – review & editing, Resources, Conceptualization, Supervision.
External commenting	-
Conflicts of interest	The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Richard T. Bryan reports a relationship with Action Bladder Cancer UK that includes: non-financial support. Richard T. Bryan reports a relationship with National Institute for Health and Care Research that includes: funding grants. Richard T. Bryan reports a relationship with Cancer Research UK that includes: funding grants. Richard T. Bryan reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Richard T. Bryan reports a relationship with Nonacus Ltd that includes: consulting or advisory. Richard T. Bryan reports a relationship with Cystotech ApS that includes: consulting or advisory. Richard T. Bryan reports a relationship with AstraZeneca Pharmaceuticals LP that includes: speaking and lecture fees. Katja K.H. Aben reports a relationship with Astellas Pharma US Inc that includes: funding grants. Katja K.H. Aben reports a relationship with Merck & Co Inc that includes: funding grants. Katja K.H. Aben reports a relationship with MSD that includes: funding grants. Katja K.H. Aben reports a relationship with Janssen Pharmaceuticals Inc that includes: funding grants. Katja K.H. Aben reports a relationship with AstraZeneca Pharmaceuticals LP that includes: funding grants. Richard T. Bryan has patent #GB2581967 issued to University of Birmingham. Richard T. Bryan has patent #WO2020070491A1 issued to University of Birmingham. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Read more	Comprehensive genome-wide association study into multiple recurrence and progression risk in non-muscle invasive bladder cancer - ScienceDirect
Contact	jasper.hof@qgg.au.dk