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Driver mutations in ADGRL3 are involved in the evolution of ependymoma

Abstract

Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n = 36), as compared with normal brain tissue (n = 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.

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Fig. 1: Clinical progression of the patient.
Fig. 2: Pathological and molecular characteristics of the tumors.
Fig. 3: Genomic features of the patient.
Fig. 4: ADGRL3 mutation in the patient.
Fig. 5: Expression level of ADGRL3 and its role in patients’ prognosis.

Data availability

The datasets used and/or analyzed in the current study are available from the corresponding author on reasonable request or through Research Data Deposit (http://www.researchdata.org.cn), the approval number is RDDB2020000810.

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Funding

This study was supported by grants from the National Natural Science Foundation of China (82073109, 81872059, 81772677, 81772675, 81572479, 81372685, and 81101521), the Guangzhou Science Technology and Innovation Project (201508020125), the Science and Technology Planning Project of Guangzhou (2016A020213004), the Natural Science Foundation of Guangdong Province (2016A030313309). All these funding had no influential role in the study design, data collection, analysis, data interpretation or writing of the report.

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Z.P.C., J.W., S.-Y.X., Q.Z., and K.S. conceived and designed the project. H.-P.C., F.W., H.-J.H., Y.-Y.Z., Z.-H.Y., F-.R.C., and H.-K.S. developed and performed the functional experiments. J.W., J.Z., C.K., X.-H.Z., F.-H.L., C.-C.G., Y.-C.L.., C.L., H.-T.X., F.H., Z.-J.L., K.S., and Z.P.C. provided medical care and managed patients. J.W., S.-Y.X., Q.Z., H.-P.C., F.W., H.-J.H., Y.-Y.Z., K.S., and Z.P.C. analyzed and interpreted data. Q.C., H.-M.W., Y.-H.L., Z.L., J.Z. provided materials and technical support. J.W., Z.P.C., S.-Y.X., Q.Z., and K.S. wrote, reviewed and revised the manuscript.

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Correspondence to Jing Wang, Ke Sai or Zhong-ping Chen.

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This work has been approved by the ethics committee and institutional review board of Sun Yat-sen University Cancer Center.

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Wang, J., Xi, Sy., Zhao, Q. et al. Driver mutations in ADGRL3 are involved in the evolution of ependymoma. Lab Invest 102, 702–710 (2022). https://doi.org/10.1038/s41374-021-00721-3

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