Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Acta Neuropathol Commun. 2018 Nov 12;6(1):123. doi: 10.1186/s40478-018-0623-0.
Mutations in SETD2 are found in many tumors, including central nervous system (CNS) tumors. Previous work has shown these mutations occur specifically in high grade gliomas of the cerebral hemispheres in pediatric and young adult patients. We investigated SETD2 mutations in a cohort of approximately 640 CNS tumors via next generation sequencing; 23 mutations were detected across 19 primary CNS tumors. Mutations were found in a wide variety of tumors and locations at a broad range of allele frequencies. SETD2 mutations were seen in both low and high grade gliomas as well as non-glial tumors, and occurred in patients greater than 55 years of age, in addition to pediatric and young adult patients. High grade gliomas at first occurrence demonstrated either frameshift/truncating mutations or point mutations at high allele frequencies, whereas recurrent high grade gliomas frequently harbored subclones with point mutations in SETD2 at lower allele frequencies in the setting of higher mutational burdens. Comparison with the TCGA dataset demonstrated consistent findings. Finally, immunohistochemistry showed decreased staining for H3K36me3 in our cohort of SETD2 mutant tumors compared to wildtype controls. Our data further describe the spectrum of tumors in which SETD2 mutations are found and provide a context for interpretation of these mutations in the clinical setting.
SETD2 突变存在于许多肿瘤中，包括中枢神经系统（CNS）肿瘤。先前的研究表明，这些突变特异性地发生在儿科和年轻成年患者的大脑半球高级别胶质瘤中。我们通过下一代测序研究了大约 640 例 CNS 肿瘤的 SETD2 突变；在 19 例原发性 CNS 肿瘤中检测到 23 个突变。突变发生在各种肿瘤和广泛的位置，具有广泛的等位基因频率。SETD2 突变可见于低级别和高级别胶质瘤以及非神经胶质瘤肿瘤，并且发生在年龄大于 55 岁的患者中，除了儿科和年轻成年患者。首次出现的高级别神经胶质瘤表现为移码/截断突变或高频等位基因突变，而复发性高级别神经胶质瘤在高频突变负荷的情况下，常带有 SETD2 点突变的亚克隆，其等位基因频率较低。与 TCGA 数据集的比较显示出一致的结果。最后，免疫组化显示我们的 SETD2 突变肿瘤队列中 H3K36me3 的染色减少，与野生型对照相比。我们的数据进一步描述了存在 SETD2 突变的肿瘤谱，并为临床环境中这些突变的解释提供了背景。
