A Genome Wide Association Study of Radiotherapy Induced Toxicity in Head and Neck Cancer Patients Identifies a Susceptibility Locus Associated with Mucositis1
What is the background of the study?
Our research department has a four decade-long focus on radiotherapy-induced morbidity. The first steps towards a multi-disciplinary approach were taken with the establishment of the Danish Head and Neck Cancer Group (DAHANCA) in 19762. This provided a nascent platform for health care professionals to join forces in the management of head- and neck cancer and to establish collaborative research projects. As part of these efforts comprehensive treatment guidelines were developed and a nation-wide data base was established. An extensive resource of clinical data including detailed recordings of normal tissue toxicity after radiotherapy for head and neck cancer from a large number of patients was available through this platform.
With the turn of the millennium, technological breakthroughs brought life to a new research area; Radiogenomics – the studies of associations between DNA variation and response to radiotherapy in the normal tissues (side-effects) and in the tumour (intended effects). The underlying assumption is that normal tissue toxicity after radiotherapy should be regarded as a complex trait dependent on a larger number of sequence alterations including single nucleotide polymorphisms (SNPs).
The Radiogenomics Consortium (RgC)
In 2009, an international Radiogenomics Consortium (RgC) was established3,4 with a set assignment to facilitate research into genotype-phenotype associations in normal tissue radiobiology. This provided a platform for us to enter in a collaborative project with Strangeways Research Laboratories, Centre for Cancer Genetic Epidemiology, University of Cambridge to conduct a genome-wide study (GWAS) to analyse associations between normal germline DNA variation and radiotherapy-induced morbidity.
Another very fruitful consequence of this new collaboration was a joint venture with the University Medical Center Groningen (UMCG) in the establishment of a head- and neck cancer group within the RgC (HN-RgC). A formal kick-off meeting was held in Manchester Cancer Research Centre in 2018 with research groups from Canada, Spain, UK, the Netherlands, Belgium and Singapore represented. The picture shows the main part of the group, happy and relieved to have taken the first steps forwards to a formal collaborative group.
Our GWAS in radiogenomics
First, we conducted an explorative discovery study, testing associations in 1,183 patients treated within DAHANCA protocols and with available biomaterial. During this process, our collaboration expanded and led to include a replication study in an independent Dutch cohort of 597 HNC patients treated within the University Medical Center Groningen (UMCG) protocols. If associations were replicated, summary data obtained from discovery and replication studies were meta-analysed.
So, what did we find in the GWAS?
We identified and replicated a significant association between a locus on chromosome 5 and radiotherapy-induced oral mucositis with a pooled OR for rs1131769*C in meta-analysis = 1.95 (95%CI 1.48-2.41; Ppooled = 4.34∙10-16). The Manhattan plot from the discovery study shows the locus passing a genome-wide significance threshold of P<5·10-8.
And what now?
Well, as in every study, this must be further independently verified. The next move in the HN-RgC, is a current meta-GWAS analysis of our combined cohorts. We collaborate through monthly web-based meetings and our group is open to every researcher working with radiotherapy in head-and neck cancer patients and with available germline biomaterial. More details on this group will be published in 2022. In the meantime, if you are interested in learning more about our group and to enter collaborative projects, you are most welcome and we can be contacted at:
Behrooz Alizadeh: firstname.lastname@example.org
Nicolaj Andreassen: email@example.com
or through myself, Line Schack, at firstname.lastname@example.org
- Schack, L. M. H. et al. A genome-wide association study of radiotherapy induced toxicity in head and neck cancer patients identifies a susceptibility locus associated with mucositis. Br. J. Cancer (2022).
- Overgaard, J., Jovanovic, A., Godballe, C. & Grau Eriksen, J. The Danish Head and Neck Cancer database. Clin. Epidemiol. Volume 8, 491–496 (2016).
- West, C. et al. Establishment of a Radiogenomics Consortium. Int. J. Radiat. Oncol. Biol. Phys. 76, 1295–6 (2010).
- West, C. & Rosenstein, B. S. Establishment of a radiogenomics consortium. Radiother. Oncol. 94, 117–118 (2010).