Department of Pediatric Hematology/Oncology, Albany Medical College, Albany Medical Center, Albany, New York.
Pathology and Diagnostic Medicine, Foundation Medicine, Inc., Morrisville, North Carolina.
Pediatr Blood Cancer. 2020 Jul;67(7):e28338. doi: 10.1002/pbc.28338. Epub 2020 May 9.
Tumor mutational burden (TMB) and driver mutations are potential biomarkers to guide targeted therapy selection. Malignant gliomas with high TMB in children may preferentially benefit from treatment with immune checkpoint inhibitors (ICPIs). Higher TMB may relate to lower incidence of driver mutations, but this relationship has not been studied in pediatric brain tumors.
Comprehensive genomic profiling was performed on 723 pediatric (≤21 years) brain tumor samples using DNA extracted from formalin-fixed paraffin-embedded tissue. TMB was calculated as mutations per megabase and categorized as low (0-6), intermediate (6-20), or high (>20). Analysis included 80 clinically relevant driver mutations; genomic alterations known to confer a selective growth advantage.
Of 723 brain tumors, TMB was low in 91.8%, intermediate in 6.1%, and high in 2.1%. In the high TMB cohort, 93% of tumors harbored a driver mutation; 70% and 63% in the intermediate and low TMB cohorts, respectively (P < 0.05). However, when excluding tumor suppressor genes, high TMB tumors had a decreased incidence of driver mutations (P < 0.001). BRAF alterations were not identified in high TMB tumors, but were enriched in low TMB tumors (P < 0.01). Conversely, there was an association between high TMB tumors and TP53 mutations (P < 10 ). Of the 15 tumors with high TMB, 14 were high-grade gliomas and 13 had alterations in TP53. Three homozygous mismatch repair deletions identified were associated with a higher TMB (P < 0.01).
Specific driver mutations appear to have a relationship with TMB. These represent populations in which ICPIs may be more or less effective.
肿瘤突变负担（TMB）和驱动基因突变是指导靶向治疗选择的潜在生物标志物。儿童中 TMB 较高的恶性神经胶质瘤可能优先受益于免疫检查点抑制剂（ICPIs）治疗。较高的 TMB 可能与较低的驱动基因突变发生率相关，但尚未在儿科脑肿瘤中对此进行研究。
对 723 例（≤21 岁）儿童脑肿瘤样本的福尔马林固定石蜡包埋组织进行了全面的基因组分析。TMB 计算为每兆碱基的突变数，并分为低（0-6）、中（6-20）或高（>20）。分析包括 80 种具有临床意义的驱动基因突变；已知赋予选择性生长优势的基因组改变。
在 723 例脑肿瘤中，TMB 低者占 91.8%，中者占 6.1%，高者占 2.1%。在高 TMB 组中，93%的肿瘤存在驱动基因突变；中间 TMB 组和低 TMB 组分别为 70%和 63%（P<0.05）。然而，当排除肿瘤抑制基因时，高 TMB 肿瘤的驱动基因突变发生率降低（P<0.001）。在高 TMB 肿瘤中未发现 BRAF 改变，但在低 TMB 肿瘤中富集（P<0.01）。相反，高 TMB 肿瘤与 TP53 突变之间存在关联（P<10）。在 15 例 TMB 较高的肿瘤中，14 例为高级别神经胶质瘤，13 例存在 TP53 改变。鉴定出的 3 例纯合性错配修复缺失与较高的 TMB 相关（P<0.01）。
特定的驱动基因突变似乎与 TMB 有关。这些代表了 ICPIs 可能更有效或不太有效的人群。
