Investigating Genetic Changes in Neuroblastoma

Tumors are heterogeneous, meaning different parts of the same tumor may be genetically different. This phenomenon, known as intratumor heterogeneity, is steadily gaining significance in the field of cancer research. Cellular and molecular differences within the same tumor play an important role in many different cancers because of their implications for the diagnosis and use of targeted therapies. According to a recently published study by Charité, the MDC and the German Cancer Consortium (DKTK), this also applies to neuroblastoma, a malignant solid tumor of the peripheral nervous system that is relatively common in children. Neuroblastomas develop from groups of immature nerve cells, usually in the adrenal glands or along the spine, from where they spread into the abdominal cavity.

Summarizing the researchers’ key findings, the study’s lead author, Dr. Karin Schmelz from Charité’s Department of Pediatric Oncology and Hematology: “In our study, we were able to show that the genetic changes typically associated with neuroblastoma can both disappear and arise over the course of the disease. These mutations are not evenly distributed across the tumor; rather they occur in different sections or even in individual cells, giving the tumor a mosaic-like appearance.

“Cancer is driven by evolutionary processes,” says Dr. Roland Schwarz, group leader of MDC’s Evolutionary and Cancer Genomics research group and one of the last authors of the study. Cancer cells undergo constant genetic changes; they are engaged in a fight for survival, including against other cancer cells. Each cancer has its own phylogenetic tree, which represents the way a tumor evolves; some cancer cells spread, while others develop resistance to therapy.

The researchers analyzed a total of 140 neuroblastoma samples. The biopsy samples were collected from 10 pediatric patients at various points during the clinical course and covered multiple tumor areas. Sample analysis involved the use of multiple modern sequencing techniques followed by computer aided evaluation.

The researchers focused their analysis on the neuroblastoma-associated genes ALK, MYCN and FGFR1, which play important roles in both the clinical course and treatment. According to their results, changes in the ALK and MYCN genes were not continuously present over the course of the disease, nor were they found in all tumor cells. Alterations in the ALK and FGFR1 genes may provide useful treatment targets, especially in relapsed patients. The researchers found that in some patients, the ALK mutations that were present at the time of diagnosis had disappeared by the time the tumor was surgically removed. In addition, changes in the FGFR1 gene were only found in several tumor regions. The researchers were also able to identify an instability in the number of gene copies present in neuroblastoma cells. In some cases, clones of cancer cells showed early deviation from the primary tumor and broke away to infiltrate other organs where they metastasized.

“The process of capturing detailed spatial and temporal changes in the copy numbers of specific genes is extremely complex,” explains bioinformatics expert Dr. Black out. Despite these challenges, his research group developed an algorithm capable of producing an accurate reconstruction of these copy numbers. In 2020, Dr. Schwarz and his international colleagues developed this method to produce evidence of continuous structural evolution in a range of different cancers. “We’ve now been able to extend this to neuroblastoma, where we were able to show in detail how the cancer genome undergoes structural changes,” said Dr. Schwarz.

Last author Prof. dr. dr. Angelika Eggert, head of Charité’s Pediatric Oncology and Hematology Department, explains: “We are now in a better position to understand how neuroblastoma cells behave. This knowledge is essential for patients with recurrence of their disease, as their treatment often requires the use of personalized and targeted therapies. When a tumor is genetically heterogeneous, targeted molecular therapy can capture most of the abnormal tissue, but, crucially, not all of the affected cells. The cancer can then grow back from those remaining cells.”

Prof. dr. Eggert explains the importance of their research in the light of the existing knowledge, saying: “Our findings are less relevant for the diagnosis of neuroblastoma and the selection of therapies. This is because the diagnosis is already reliable, thanks to technologies that use decades of tests such as imaging, urine tests and single tissue biopsies, and because chemotherapy targeting fast-growing cells remains the treatment of choice for the primary tumor, however, if the disease recurs after treatment, targeted treatment options become particularly important. based on a single tissue biopsy from a single tumor region adequately addresses tumor genetic heterogeneity, therefore, when relapse occurs, we should consider using state-of-the-art sequencing techniques to analyze tumor tissue samples harvested from multiple regions This would give us as much as possible the provide details about the disease, allowing us to further improve the decision-making process regarding the selection of personalized therapies.”

The researchers are now testing other methods in hopes of solving some of the remaining technical challenges. These include the use of single-cell technologies and liquid biopsies, a new type of blood test that analyzes genetic information released into the bloodstream by tumors. Taking advantage of the analysis of multiple blood samples over the course of the disease, these techniques will provide evidence of any genetic changes that are taking place — without the need for invasive surgical biopsies. Both techniques and their clinical application are intensively studied at Charité, the Berlin Institute of Health in Charité (BIH) and the MDC.

Reference: Schmelz K, Toedling J, Huska M, et al. Spatial and temporal intratumor heterogeneity has potential implications for neuroblastoma treatment decisions based on single biopsy. Nat Comm. 2021;12(1):6804. doi: 10.1038/s41467-021-26870-z

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