PMID- 29948154 OWN - NLM STAT- MEDLINE DCOM- 20191025 LR - 20191025 IS - 1432-0533 (Electronic) IS - 0001-6322 (Linking) VI - 136 IP - 4 DP - 2018 Oct TI - Pediatric low-grade gliomas can be molecularly stratified for risk. PG - 641-655 LID - 10.1007/s00401-018-1874-3 [doi] AB - 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. FAU - Yang, Rui Ryan AU - Yang RR AD - 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. AD - Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China. AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Aibaidula, Abudumijiti AU - Aibaidula A AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Wang, Wei-Wei AU - Wang WW AD - Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Jian She Dong Road 1, Zhengzhou, 450001, Henan, China. FAU - Chan, Aden Ka-Yin AU - Chan AK AD - 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. FAU - Shi, Zhi-Feng AU - Shi ZF AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Zhang, Zhen-Yu AU - Zhang ZY AD - Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road 1, Zhengzhou, 450001, Henan, China. FAU - Chan, Danny Tat Ming AU - Chan DTM AD - Department of Neurosurgery, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China. FAU - Poon, Wai Sang AU - Poon WS AD - Department of Neurosurgery, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China. FAU - Liu, Xian-Zhi AU - Liu XZ AD - Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Jianshe Dong Road 1, Zhengzhou, 450001, Henan, China. FAU - Li, Wen-Cai AU - Li WC AD - Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Jian She Dong Road 1, Zhengzhou, 450001, Henan, China. FAU - Zhang, Rui-Qi AU - Zhang RQ AD - 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. FAU - Li, Yan-Xi AU - Li YX AD - 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. FAU - Chung, Nellie Yuk-Fei AU - Chung NY AD - 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. AD - Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China. FAU - Chen, Hong AU - Chen H AD - Department of Pathology, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Wu, Jingsong AU - Wu J AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Zhou, Liangfu AU - Zhou L AD - Department of Neurosurgery, Huashan Hospital, Fudan University, Wulumuqi Zhong Road 12, Shanghai, 200040, China. FAU - Li, Kay Ka-Wai AU - Li KK AD - 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. kayli@cuhk.edu.hk. AD - Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China. kayli@cuhk.edu.hk. FAU - Ng, Ho-Keung AU - Ng HK AD - 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. hkng@cuhk.edu.hk. AD - Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China. hkng@cuhk.edu.hk. LA - eng GR - 02133146/Health and Medical Research Fund/International GR - 2151229/S. K. Yee Medical Foundation, HK/International GR - JCYJ20170307165432612/Shenzhen Science Technology and Innovation Commission/International GR - 201540145/Shanghai Municipal Commission of Health and Family Planning/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180614 PL - Germany TA - Acta Neuropathol JT - Acta neuropathologica JID - 0412041 RN - 0 (Biomarkers, Tumor) SB - IM MH - Adolescent MH - Biomarkers, Tumor MH - Brain Neoplasms/*pathology MH - Child MH - Child, Preschool MH - Cohort Studies MH - Female MH - Glioma/*pathology MH - Humans MH - Immunohistochemistry MH - Infant MH - Infant, Newborn MH - Male MH - Mutation/genetics MH - Neoplasm Grading/*methods MH - Pathology, Molecular MH - Pediatrics MH - Prognosis MH - Progression-Free Survival MH - Risk Assessment MH - Survival Analysis MH - Treatment Outcome OTO - NOTNLM OT - ATRX OT - BRAF OT - CDKN2A OT - H3F3A OT - Molecular risk stratification OT - Pediatric low-grade gliomas EDAT- 2018/06/28 06:00 MHDA- 2019/10/28 06:00 CRDT- 2018/06/28 06:00 PHST- 2017/12/21 00:00 [received] PHST- 2018/06/05 00:00 [accepted] PHST- 2018/06/28 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/06/28 06:00 [entrez] AID - 10.1007/s00401-018-1874-3 [pii] AID - 10.1007/s00401-018-1874-3 [doi] PST - ppublish SO - Acta Neuropathol. 2018 Oct;136(4):641-655. doi: 10.1007/s00401-018-1874-3. Epub 2018 Jun 14.