Rees Donald, Gianferante D Matthew, Kim Jung, Stavrou Theodora, Reaman Gregory, Sapkota Yadav, Gramatges M Monica, Morton Lindsay M, Hudson Melissa M, Armstrong Gregory T, Freedman Neal D, Huang Wen-Yi, Diver W Ryan, Lori Adriana, Luo Wen, Hicks Belynda D, Liu Jia, Hutchinson Amy A, Goldstein Alisa M, Mirabello Lisa
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Rockville, MD, United States.
Department of Pediatric Hematology and Oncology, Walter Reed National Military Medical Center, Bethesda, MD, United States.
Front Oncol. 2024 Aug 9;14:1441958. doi: 10.3389/fonc.2024.1441958. eCollection 2024.
Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in , , , , , and predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions.
Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes (, , , , , were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls.
Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were p=3.0x10) and (p=1.4x10).
Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.
髓母细胞瘤是儿童最常见的恶性脑肿瘤。大多数病例为散发性，但在 、 、 、 、 和 中具有特征明确的种系改变易患髓母细胞瘤。然而，关于易患髓母细胞瘤的致病/可能致病（P/LP）变异的知识因评估的基因、患者人口统计学和致病性定义而异。
对 160 名髓母细胞瘤儿童幸存者进行种系外显子测序。分析集中在 239 个已知癌症易感基因（CSG）中的罕见变异。使用 ClinVar 和 InterVar 鉴定 P/LP 变异。对已知髓母细胞瘤易感基因（ 、 、 、 、 、 ）中意义未明的变异进一步分类为功能丧失变异。我们将病例中 P/LP 变异的频率与 1259 名无癌成年对照中的频率进行比较。
20 例（12.5%）在常染色体显性 CSG 中有 P/LP 变异，而对照中为 5%（p = 1.0×10），其中 10 例（6.3%）是已知髓母细胞瘤基因中的 P/LP 变异，显著高于对照中观察到的 0.2%（p = 1.4×10）。病例中 P/LP 变异最多且显著高于对照的 CSG 是 （p = 3.0×10）和 （p = 1.4×10）。
约八分之一的儿童髓母细胞瘤幸存者有常染色体显性 P/LP CSG 变异。我们确认了几个已知的相关基因，并鉴定出可能在髓母细胞瘤中起重要作用的新基因。
