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Pediatric low-grade gliomas can be molecularly stratified for risk

  • Rui Ryan Yang
  • Abudumijiti Aibaidula
  • Wei-wei Wang
  • Aden Ka-Yin Chan
  • Zhi-feng Shi
  • Zhen-yu Zhang
  • Danny Tat Ming Chan
  • Wai Sang Poon
  • Xian-zhi Liu
  • Wen-cai Li
  • Rui-qi Zhang
  • Yan-Xi Li
  • Nellie Yuk-Fei Chung
  • Hong Chen
  • Jingsong Wu
  • Liangfu Zhou
  • Kay Ka-Wai Li
  • Ho-Keung Ng
Original Paper

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.

Keywords

Pediatric low-grade gliomas H3F3A ATRX BRAF CDKN2A Molecular risk stratification 

Notes

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Rui Ryan Yang
    • 1
    • 2
    • 3
  • Abudumijiti Aibaidula
    • 3
  • Wei-wei Wang
    • 4
  • Aden Ka-Yin Chan
    • 1
  • Zhi-feng Shi
    • 3
  • Zhen-yu Zhang
    • 5
  • Danny Tat Ming Chan
    • 6
  • Wai Sang Poon
    • 6
  • Xian-zhi Liu
    • 5
  • Wen-cai Li
    • 4
  • Rui-qi Zhang
    • 1
  • Yan-Xi Li
    • 1
  • Nellie Yuk-Fei Chung
    • 1
    • 2
  • Hong Chen
    • 7
  • Jingsong Wu
    • 3
  • Liangfu Zhou
    • 3
  • Kay Ka-Wai Li
    • 1
    • 2
  • Ho-Keung Ng
    • 1
    • 2
  1. 1.Department of Anatomical and Cellular PathologyThe Chinese University of Hong Kong, Prince of Wales HospitalShatinChina
  2. 2.Shenzhen Research InstituteThe Chinese University of Hong KongShenzhenChina
  3. 3.Department of Neurosurgery, Huashan HospitalFudan UniversityShanghaiChina
  4. 4.Department of PathologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  5. 5.Department of NeurosurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
  6. 6.Department of NeurosurgeryThe Chinese University of Hong Kong, Prince of Wales HospitalShatinChina
  7. 7.Department of Pathology, Huashan HospitalFudan UniversityShanghaiChina

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