Mistry Matthew, Zhukova Nataliya, Merico Daniele, Rakopoulos Patricia, Krishnatry Rahul, Shago Mary, Stavropoulos James, Alon Noa, Pole Jason D, Ray Peter N, Navickiene Vilma, Mangerel Joshua, Remke Marc, Buczkowicz Pawel, Ramaswamy Vijay, Guerreiro Stucklin Ana, Li Martin, Young Edwin J, Zhang Cindy, Castelo-Branco Pedro, Bakry Doua, Laughlin Suzanne, Shlien Adam, Chan Jennifer, Ligon Keith L, Rutka James T, Dirks Peter B, Taylor Michael D, Greenberg Mark, Malkin David, Huang Annie, Bouffet Eric, Hawkins Cynthia E, Tabori Uri
Matthew Mistry, Nataliya Zhukova, Daniele Merico, Rahul Krishnatry, Mary Shago, James Stavropoulos, Noa Alon, Peter N. Ray, Vilma Navickiene, Joshua Mangerel, Marc Remke, Vijay Ramaswamy, Ana Guerreiro Stucklin, Martin Li, Edwin J. Young, Cindy Zhang, Pedro Castelo-Branco, Doua Bakry, Suzanne Laughlin, James T. Rutka, Peter B. Dirks, Michael D. Taylor, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori; The Hospital for Sick Children; Matthew Mistry, Patricia Rakopoulos, Rahul Krishnatry, Joshua Mangerel, Pawel Buczkowicz, Ana Guerreiro Stucklin, Doua Bakry, Adam Shlien, Mark Greenberg, David Malkin, Annie Huang, Eric Bouffet, Cynthia E. Hawkins, and Uri Tabori, University of Toronto; Jason D. Pole, Pediatric Oncology Group of Ontario, Toronto, Ontario; Jennifer Chan, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Pedro Castelo-Branco, Universidade do Algarve, Faro, Portugal; Keith L. Ligon, Dana-Farber/Boston Children's Cancer Center, Boston, MA.
J Clin Oncol. 2015 Mar 20;33(9):1015-22. doi: 10.1200/JCO.2014.58.3922. Epub 2015 Feb 9.
To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG).
We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained.
sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024).
BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.
揭示导致小儿低级别胶质瘤（PLGG）转化为继发性高级别胶质瘤（sHGG）的基因事件。
我们从一个对886例PLGG患者进行长期临床随访的基于人群的队列中，回顾性地确定了sHGG患者。对可用样本进行外显子组测序和阵列比较基因组杂交（array CGH），随后对整个sHGG队列进行详细的基因分析。获取了基因不同亚组的临床和结局数据。
在2.9%的PLGG中观察到sHGG（886例患者中的26例）。与原发性小儿高级别胶质瘤（HGG）患者相比，sHGG患者非沉默体细胞突变的频率较高（中位数，每个外显子组25个突变；P = 0.0042）。常见染色质修饰基因和端粒维持途径的改变，而没有sHGG携带BRAF-KIAA1549融合基因。最常见的改变分别是BRAF V600E和CDKN2A缺失，在39%和57%的sHGG中出现。重要的是，所有BRAF V600E和80%的CDKN2A改变都可以追溯到其对应的PLGG。BRAF V600E将sHGG与原发性HGG区分开来（P = 0.0023），而BRAF和CDKN2A改变在未转化的PLGG中较少见（分别为P < 0.001和P < 0.001）。携带BRAF突变的PLGG转化的潜伏期比野生型PLGG长（中位数分别为6.65年[范围，3.5至20.3年]对1.59年[范围，0.32至15.9年]；P = 0.0389）。此外，BRAF突变型和野生型肿瘤患儿的5年总生存率分别为75%±15%和29%±12%（P = 0.024）。
BRAF V600E突变和CDKN2A缺失构成sHGG的一种临床独特亚型。BRAF V600E PLGG转化过程的延长为手术干预、监测和靶向治疗提供了机会，以减轻sHGG的结局。
