Journal
CANCERS
Volume 13, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/cancers13061377
Keywords
DNA methylation; pediatric CNS tumors; tumor classification; copy-number variation; integrated diagnosis; molecular pathology
Categories
Funding
- SFCE (Societe Francaise de lutte contre les Cancers de l'Enfant)
- French Institut National du Cancer [2019-29]
- Association Cassandra
- Liv' et Lumiere foundation
- Toulouse Recherche Enfants Cancer (TREC) foundation
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Implementing DNA methylation profiling in the diagnostic process of challenging pediatric CNS tumors led to significant diagnostic refinements and amendments, supporting the use of DNA methylation as a complementary tool for conventional histopathological diagnosis. The study highlights the impact of DNA methylation testing in improving diagnostic accuracy and guiding patient management decisions for pediatric CNS tumors with diagnostic uncertainty.
Simple Summary Supported by the easy-to-use and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts-including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH-62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ classifier and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores <0.84 (74.3%). (3) CNV investigations also evidenced alterations used for diagnosis and prognostication. (4) A diagnosis was finally established for 44 tumors (71%). Our results support the use of DNA methylation for challenging pediatric tumors. We demonstrated how additional methylation-based analyses complement the classifier score to support conventional histopathological diagnosis.
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