Pediatric low-grade gliomas can be molecularly stratified for risk

Springer Science and Business Media LLC - Tập 136 - Trang 641-655 - 2018
Rui Ryan Yang1,2,3, Abudumijiti Aibaidula3, Wei-wei Wang4, Aden Ka-Yin Chan1, Zhi-feng Shi3, Zhen-yu Zhang5, Danny Tat Ming Chan6, Wai Sang Poon6, Xian-zhi Liu5, Wen-cai Li, Rui-qi Zhang1, Yan-Xi Li1, Nellie Yuk-Fei Chung1,2, Hong Chen7, Jingsong Wu3, Liangfu Zhou3, Kay Ka-Wai Li1,2, Ho-Keung Ng1,2
1Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, China
2Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
3Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
4Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
5Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
6Department of Neurosurgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, China
7Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

Tóm tắt

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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