The evolution of the tumour

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Study on genetic alterations in neuroblastoma

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Berlin, 23.11.2021 – If the genetic material of the cells within a tumour differs, this is called intratumoral genetic heterogeneity. Researchers at Charité – Universitätsmedizin Berlin and the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) have now reconstructed how this develops in the course of the disease in neuroblastoma – a cancer that occurs mainly in early childhood. They show that a single tumour can have large genetic differences: both spatially and temporally. The study has been published in the journal Nature Communications*.

Tumours are heterogeneous: they can differ genetically from each other in different parts of the tumour. This phenomenon of intratumoral genetic heterogeneity is becoming increasingly important in cancer research. Cellular and molecular differences within a tumour play an important role in many cancers, as they can affect diagnostics as well as the use of targeted therapies. This publication by Charité, MDC and the German Consortium for Translational Cancer Research now proves this: This also applies to neuroblastomas. The malignant, solid tumours of the peripheral nervous system are a relatively common cancer in children. They usually originate from nerve cell bundles in the adrenal glands or along the spinal column and then spread to the abdominal cavity.

„With our work, we can show that genetic mutations that are typical of neuroblastoma can disappear again during the course of the disease or that new ones can arise. Moreover, these mutations do not occur evenly distributed in the tumour, but only in individual areas or even only in individual cells of a tumour. They present themselves like a mosaic,“ says Dr Karin Schmelz, first author of the study from the Clinic for Paediatrics with a focus on Oncology and Haematology at the Charité, summarising the central finding.

„Cancer is driven by evolutionary processes,“ says Dr Roland Schwarz, head of the „Evolutionary and Cancer Genomics“ research group at the MDC and one of the final authors. The cells continuously change their genetic composition and fight for survival, even among themselves. They each have their own pedigrees, some later form metastases or become more difficult to treat.

The research group examined a total of 140 neuroblastoma samples. These came from spatially different areas of the tumour and were taken from a total of ten children during the course of the diseases. The team used several modern sequencing methods on individual tissue samples as well as computer-assisted analyses for the evaluation.

The researchers examined the genes ALK, MYCN and FGFR1, which are important for the course and therapy of the disease, in particular detail. Their results: ALK and MYCN were not consistently found during the disease and not in all cells of the tumour. Changes in the ALK and FGFR1 genes can be a target for therapy, especially when the disease recurs. The researchers found that ALK mutations were present in some patients when the disease was diagnosed, but were no longer present at the time the tumour was surgically removed. In addition, the changes in the FGFR1 gene were only found in individual areas of the tumour. In addition, the researchers were able to demonstrate instability in the number of gene copies of the neuroblastoma cells. In individual cases, cancer cell clones developed differently from the original tumour at an early stage and passed on to other organs as daughter cells, thus forming metastases.

„Detecting changes in the copy number of certain genes in high spatial and temporal resolution is very complex,“ explains bioinformatician Dr Schwarz. His research group has developed an algorithm that can nevertheless reconstruct these copy numbers highly precisely. With the help of this method, Dr Schwarz and his international colleagues demonstrated the continuous structural evolution in different types of cancer in 2020. „We have now also been able to prove this for neuroblastoma and show in detail how the cancer genome changes structurally,“ says Dr Schwarz.

Prof. Dr. Angelika Eggert, Director of the Clinic for Paediatrics with a focus on Oncology and Haematology at Charité and last author of the study, explains: „We can now better understand how the cells of neuroblastoma behave. This knowledge is essential for our patients who suffer a relapse of the diseases, because then personalised, targeted therapies are often used. However, if the tumour presents as genetically diverse, molecularly targeted treatment may be able to capture much of the diseased tissue, but not all of the cells. From the remaining cells, the cancer can grow again.“

However, she also emphasises, „Our results are less relevant for diagnosis and choice of therapy in initial treatment, because the diagnosis of neuroblastoma can be reliably made using methods that have been tried and tested for decades – such as imaging, urine tests and also with a single tissue sample. For treatment in the initial phase of the disease, chemotherapy, which targets all fast-growing cells, remains the drug of choice. However, if the disease recurs afterwards, targeted therapy becomes particularly important. Selecting therapy based on a single piece of tissue from only one site of the tumour probably does not do justice to the genetic diversity of the tumour. So for the future, in the event of a relapse, we should consider examining the tumour tissue at multiple sites using the latest sequencing techniques. This would give us the most precise information possible about the disease to make even better personalised treatment decisions.“

Since this is currently still associated with technical challenges, the scientists are examining other methodological possibilities, including the use of single-cell technologies and liquid biopsies. These are novel blood tests to examine the genetic material that a tumour releases into the blood. Using several blood samples during the course of the disease, changes in the genes can be detected – without the need for a surgically removed tissue sample. Both methods and their clinical use are already being intensively researched at the Charité, the Berlin Institute of Health at the Charité (BIH) and the MDC.

*Schmelz K et al. Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions. Nature Communications (2021), doi: 10.1038/s41467-021-26870-z

Caption: Processing tumour tissue for sequencing: For a sensitive analysis of genetic heterogeneity, the researchers only included areas with a high content of vital tumour cells. These were isolated from tissue sections of the frozen tumour material using a scalpel. © Charité l Linda Ambrosiu

Links:

Originalpublikation

Klinik für Pädiatrie mit Schwerpunkt Onkologie und Hämatologie

Arbeitsgruppe Schwarz am MDC

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