Detection, Classification, Characterization and Treatment Monitoring of Tumors by Accessible Epigenetic Classification (DC2M-TAEC)

A correct diagnosis is crucial for predicting prognosis and choosing treatment. Current improvements in our understanding of brain tumor biology has led to an increasing use of epigenetic diagnostics. These diagnostic strategies are based upon identification of the modification done to DNA to regulate which part of the genome that is readily available for the cells. Which genes are available for a cell defines which type of cell is present. This can thus be used to carefully characterize which tumor cells are present in a more stable manner than by other classical diagnostic strategies. Such epigenetic diagnostics can thus lead to improved prognostication and more personalized treatment. Such epigenetic classification is new and in development, and the current standard method of collecting and processing this data is slow, expensive, and resource-intensive. These limitations make it difficult to implement the process globally, negatively affecting patient care. The DC2M-TAEC project aims to change this by using a faster and more accessible technology called nanopore sequencing. This method allows for quick and simultaneous analysis of methylation and genetic sequencing without the need for complex and time-consuming procedures. Nanopore sequencing involves a PCR-free, single-molecule sequencing technique that streamlines the process. This project brings together experts from Heidelberg, Oslo, Istanbul, and Toronto to establish this method in a large medical center currently unable to perform regular molecular profiling due to existing challenges. The ultimate goal of this improved diagnostic workflow is to provide individualized and risk-adapted care for patients with brain tumors worldwide. Additionally, this project could serve as a proof of concept demonstrating the broader potential of nanopore sequencing beyond neuro-oncology, paving the way for its application in other medical fields in the future.

Understanding the epigenetics of brain tumors is vital, as it allows distinguishing tumors with unprecedented precision, guiding precise classification and tailored therapeutic approaches. A paramount tool when using DNA methylation for classification – especially for brain tumors – is the Heidelberg classifier. This computer algorithm assigns any given specimen to the correct diagnosis based on its methylation data. However, using this algorithm currently requires data input that is generated in a tedious, lengthy and costly manner. This limits its global implementation due to unavailability of resources and the time-consuming nature of the protocol, which ultimately hampers patient care. With DC2M-TAEC, we will leverage a rapid and more accessible platform to simultaneously generate methylation and sequencing results: long-read, or so called nanopore sequencing – a PCR-free, single-molecule sequencing approach. We will paradigmatically establish this method in a large center in which molecular profiling is so far not regularly available due to the aforementioned hurdles. Within this consortium, experts from Heidelberg, Oslo, Istanbul, and Toronto join forces. Ultimately, the resulting diagnostic workflow, demonstrated to be globally feasible, will allow individualized and risk-adapted care for patients with brain tumors. This tremendous translational impact is emphasized by the fact that the approaches will span early detection, surgery planning, intra-operative surgery guidance, treatment monitoring, and biological insight by detection of resistance mechanisms. This project can serve as a proof of concept to further establish nanopore sequencing beyond the field of neuro-oncology in the future.