What is the main focus of your research?

My lab focuses on precision medicine for children, adolescents, and young adults with cancer; in particular children with brain tumours. We combine approaches from population genomics, cancer genomics, and systems genetics to understand the genetic basis of cancer, the somatic evolution of cancer cells, and the mechanisms that drive genome and proteome instability in cancer. We further aim to improve the diagnosis, prognosis, and therapeutic recommendations for brain cancer patients based on the development of novel computational approaches that integrate multiple layers of molecular information.

What first drew you to this topic(s)?

A neighbouring lab at the École Polytechnique Fédérale de Lausanne (EPFL) published, during my PhD studies, a paper on genome-to-genome association analysis and demonstrated that human genetic factors influence the evolution of viral genomes. Around the same time, the first cancer genome studies were published that also demonstrated the impact of genetic variation on cancer evolution. Together, this sparked my interest to study somatic evolution and how a patient’s genetic background can affect somatic mutation landscapes in cancer cells. Fortunately for me, around the time of my graduation, the International Cancer Genome Consortium initiated a new project to study whole cancer genomes of over 2,500 cancer patients (https://www.nature.com/collections/afdejfafdb). The European Molecular Biology Laboratory (EMBL) and the German Cancer Research Center (DKFZ) in Heidelberg had major scientific and technical roles in this project, so it was the perfect place to study cancer biology and to dive into cancer genomics. I hence moved for my postdoc to Heidelberg and developed novel integrative approaches to study the interplay between patient and cancer genomes (Nature 2020). The collaborative research environment in Heidelberg and close interactions with the DKFZ exposed me to the exciting field of paediatric neuro-oncology, and I gradually shifted my research focus towards paediatric brain tumours and in particular the evolution of brain tumours in children with rare genetic disorders (Lancet Oncol 2018, J Clin Oncol 2019, Nature 2020). 

What motivates you most about your research?

A tumour can be the first disease that patients with a rare genetic disorder develop and other symptoms might be completely absent, especially in very young children. A precise and timely diagnosis is therefore important, because this information can affect treatment plans and reduce the risk of other malignancies that might develop later in life. We noticed in our studies that a clinical diagnosis for a cancer predisposition syndrome was absent in about half of all affected children that developed medulloblastoma, a malignant brain tumour. It has been thus a strong motivation to study how these tumors evolve and how to derive novel diagnostic biomarkers that can help physicians to identify patients with a rare genetic disorder. We developed a clinical decision-making algorithm that integrates clinical and molecular information and helps to identify patient groups that are at high risk of being affected by a rare genetic disorder and thus require follow-up genetic counselling. 

How might detecting a rare genetic disorder in a patient help guide their treatment?

For example, we realised that neuro-oncologists should work hand-in-hand with genetic counsellors to treat WNT-medulloblastomas. Around 8% of patients have a very high risk of developing secondary malignancies such as colorectal cancer, either around the same time or just a few years after being diagnosed with a brain tumour. These patients show typically no other clinical symptoms that might indicate a cancer predisposition syndrome and the clinical presentation of these patients is similar to sporadic cases. We studied the evolution of these brain tumours and identified that the absence of a single somatic mutation in a WNT-medulloblastoma genome is highly prognostic for identifying patients with a cancer predisposition syndrome. This somatic mutation activates a gene that drives the majority of WNT-medulloblastomas and the mutational status of this gene is routinely assessed in the clinics. Our results suggest that patients with an atypical WNT-medulloblastoma should be referred to a genetic counsellor and undergo genetic testing. Current guidelines recommend that systematic screening colonoscopies should be initiated around the age of ten to early recognise colorectal tumours; this is also the age that most children develop WNT-medulloblastomas. It has been therefore important for us to identify from our integrative genomic analyses a diagnostic biomarker that can be routinely assessed in the clinic. Patients with WNT-medulloblastoma have typically a favourable clinical outcome and it is crucial to spare these patients from secondary cancers. 

How do you feel about becoming a group leader? What do you hope to achieve in the first 5 year period?

I’m really excited to be able to build up a research program in computational oncology and to assemble a diverse team of genome scientists, bioinformaticians, and molecular biologists. It is great to have more freedom, design long-term projects, and train the next generation of researchers. I don’t like to plan too far ahead, as you never know what opportunities might become available in the near future. For example, earlier this year I have started an exciting new collaboration with the Pacific Pediatric Neuro-Oncology Consortium (pnoc.us) and research groups in Switzerland that work on aggressive paediatric brain tumours. These collaborations allow us to dive into new research areas of precision medicine and to pursue genome research in the context of clinical trials. 

What do you think cancer treatment will look like in 10 years’ time?

This is difficult to answer. I hope we will better understand the biology of childhood brain tumours within the next ten years and thus identify more personalised treatment strategies. A goal could be to take an upfront tumour biopsy, study patient- and cancer genomes as part of the standard-of-care package, and target specific pathways or molecular alterations with drugs or other treatment strategies. The complexity of cancer biology will probably also require tumour boards that are composed of experts in various fields, as well as quick translation of pre-clinical findings into early phase clinical trials. There might also be no single treatment strategy due to tumour heterogeneity within patients. Combinatorial personalised treatments might be more effective, yet will require extensive monitoring of tumour cells in blood and cerebrospinal fluid with emerging single cell sequencing technologies. 

What advice would you give to young researchers starting out in their career?

I would encourage young researchers to follow their gut instinct and study topics that they are deeply interested in. Motivation is, in my opinion, the most important factor for solving problems and developing new skills. I also think working on several projects at once helps to overcome periods where no immediate solution can be found, as some questions require longer periods of finding an answer. Another piece of advice would be to read as much literature as possible. Many problems have been already solved in other fields and can be transferred. 

What most attracted you to NCMM and Norway, and what are you most looking forward to about being based in Oslo?

I really liked that the NCMM opened a call in precision medicine with a co-affiliation at the hospital, and that several research groups at the NCMM also focus on rare diseases. This setup helps my group to work at the interface between basic and translational research and to identify clinically-relevant research projects. The 5+4 year model and a generous start-up package to set up an independent research group were also very attractive reasons for moving to Oslo. The fact that I could continue to stay connected with the EMBL via the Nordic EMBL Partnership was also a motivation to apply for this position. In terms of moving to Norway, I really enjoy living at the Oslofjord; I'm very much looking forward to learning how to kayak, and to exploring the fjord and nearby forests by bike.

Recent publications

• Waszak, Robinson, et al. Germline Elongator mutations in Sonic Hedgehog medulloblastoma. Nature(2020). 580:396–401.
• ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature (2020). 578:82–93.
• Begemann, Waszak, et al. Germline GPR161 mutations predispose to pediatric medulloblastoma. Journal of Clinical Oncology (2019). 38:43–50.
• Waszak, Northcott, et al. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. The Lancet Oncology(2018). 19:785–98.