Background

Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0–40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults.

Methods

Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0–18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18–40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0–18 years, 2015–21) and the Children's Brain Tumor Network (0–18 years, 1981–2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan–Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy.

Findings

1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2–8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1–1·1; p<0·0001 by χ² test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAF^V600E gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDH^WT and H3^WT gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7–47·7) and in malignant IDH^mut gliomas (five of eight; 62·5%, 24·5–91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDH^mut astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8–57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3–0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status.

Interpretation

Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults, is enriched in specific molecular subgroups, and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients.

Funding

The Canadian Institutes for Health Research, Stand Up to Cancer—Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation.

中文翻译：

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儿童、青少年和年轻人原发性错配修复缺陷型神经胶质瘤的前景：一项多队列研究

 背景

神经胶质瘤是儿童、青少年和年轻人（0-40 岁）癌症相关死亡的主要原因。原发性错配修复缺陷 （MMRD） 是一种泛癌机制，具有独特的生物学和治疗机会。我们旨在确定原发性 MMRD 在儿童、青少年和年轻人神经胶质瘤中的程度和影响。

 方法

临床和分子数据是从多伦多患有神经胶质瘤的儿童、青少年和年轻人的人群队列中收集的（TOR-Ped，0-18 岁，收集于 2000 年 1 月 1 日至 2021 年 12 月 31 日;和 TOR-AYA，年龄 18-40 岁，收集于 2000 年 1 月 1 日至 2019 年 6 月 30 日）。使用了来自 St Jude 儿童研究医院 （0-18 岁，2015-21） 和儿童脑肿瘤网络 （0-18 岁，1981-2021） 的额外验证儿科队列。应用功能基因组工具的主要目的是评估神经胶质瘤亚组中的主要 MMRD 患病率和种系影响。为了评估原发性 MMRD 对治疗和总生存期的影响，对接受免疫治疗的另一组原发性 MMRD 神经胶质瘤患者使用了 Kaplan-Meier 估计值。

 发现

该研究包括 1389 例神经胶质瘤。高级别胶质瘤原发性 MMRD 的患病率在 3·7% 到 12·4% 之间（总共 30 例/483;6·2%，95% CI 4·2-8·7），而低级别胶质瘤的患病率不到 1%（899 例中的 4 例;0·4%，0·1-1·1;p<0·0001，通过 χ² 检验）。所有神经胶质瘤的特异性分子分析表明，少突胶质细胞瘤 （67 个中没有） 不存在原发性 MMRD，并且在 BRAF^V600E 神经胶质瘤 （110 个中的一个） 和组蛋白突变驱动的神经胶质瘤 （150 个中的一个） 中不常见。在儿科年龄组 （<18 岁） 中，原发性 MMRD 常见于携带致病性 TP53 变异的 IDH^WT 和 H3^WT 神经胶质瘤（61 例中的 21 例;34·4%，22·7-47·7）和恶性 IDH^突变性神经胶质瘤（8 例中的 5 例;62·5%，24·5-91·5）。在 35 例原发性 MMRD 神经胶质瘤中，种系病因占 33 例 （94·3%），包括患有先前未识别的 Lynch 综合征的儿童、青少年和年轻人。原发性 MMRD 胶质瘤患者的生存率较差。与错配修复熟练的神经胶质瘤患者相比，患有原发性 MMRD 的 IDH^突变星形细胞瘤患者的生存率特别差 （HR 12·6,95% CI 2·8–57·5;p=0·0011 通过多变量 Cox 回归）。与常规放化疗方案相比，免疫检查点阻断与原发性 MMRD 神经胶质瘤患者生存率的提高相关 （HR 0·4， 0·3–0·7;p=0·0017 通过多变量 Cox 回归），无论年龄或种系状态如何。

 解释

原发性 MMRD 在儿童、青少年和年轻人的神经胶质瘤中比以前报道的更常见，在特定分子亚组中富集，并且与不良结果相关。准确检测、基因检测、通过监测进行早期诊断以及实施免疫疗法可能会提高这些患者的生存率。

 资金

加拿大卫生研究院、抗击癌症——百时美施贵宝催化剂、美国国立卫生研究院、加拿大癌症协会、加拿大脑协会、V 癌症研究基金会、BioCanRx、加拿大免疫治疗网络、Harry 和 Agnieszka Hall、Meagan's Hug、BRAINchild Canada 和 LivWise 基金会。