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Pediatric low-grade gliomas can be molecularly stratified for risk

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Abstract

Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.

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Acknowledgements

This study was supported by the Health and Medical Research Fund, Hong Kong (reference number 02133146); S. K. Yee Medical Foundation, Hong Kong (reference number 2151229); Children Cancer Foundation, Hong Kong; Shenzhen Science Technology and Innovation Commission (reference number JCYJ20170307165432612); and, Shanghai Municipal Commission of Health and Family Planning, China (reference number 201540145). We are grateful to Dr. Cynthia Hawkins, SickKids, Toronto, Canada, for allowing us to make use her NanoString panel.

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  1. Rui Ryan Yang, Abudumijiti Aibaidula, and Wei-wei Wang contributed equally.

Authors and Affiliations

  1. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China

    Rui Ryan Yang, Aden Ka-Yin Chan, Rui-qi Zhang, Yan-Xi Li, Nellie Yuk-Fei Chung, Kay Ka-Wai Li & Ho-Keung Ng

  2. Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China

    Rui Ryan Yang, Nellie Yuk-Fei Chung, Kay Ka-Wai Li & Ho-Keung Ng

  3. Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China

    Rui Ryan Yang, Abudumijiti Aibaidula, Zhi-feng Shi, Jingsong Wu & Liangfu Zhou

  4. Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Jian She Dong Road 1, Zhengzhou, 450001, Henan, China

    Wei-wei Wang & Wen-cai Li

  5. Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road 1, Zhengzhou, 450001, Henan, China

    Zhen-yu Zhang & Xian-zhi Liu

  6. Department of Neurosurgery, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China

    Danny Tat Ming Chan & Wai Sang Poon

  7. Department of Pathology, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China

    Hong Chen

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  1. Rui Ryan Yang
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Yang, R.R., Aibaidula, A., Wang, Ww. et al. Pediatric low-grade gliomas can be molecularly stratified for risk. Acta Neuropathol 136, 641–655 (2018). https://doi.org/10.1007/s00401-018-1874-3

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