Exner Nadin D, Valenzuela Jaime Alberto Campos, Abou-El-Ardat Khalil, Miletic Hrvoje, Huszthy Peter C, Radehaus Petra M, Schröck Evelin, Bjerkvig Rolf, Kaderali Lars, Klink Barbara, Nigro Janice M
Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
University of Applied Sciences Mittweida, Department of Applied Informatics & Biosciences, Mittweida, Germany.
Oncotarget. 2019 Jun 4;10(38):3641-3653. doi: 10.18632/oncotarget.26950.
We previously reported the establishment of a rare xenograft derived from a recurrent oligodendroglioma with 1p/19q codeletion. Here, we analyzed in detail the exome sequencing datasets from the recurrent oligodendroglioma (WHO grade III, recurrent O) and the first-generation xenograft (xenograft). Somatic SNVs and small InDels ( = 80) with potential effects at the protein level in recurrent O included variants in (NM_005896:c.395G>A; p. Arg132His), (NM_003902:c.1307_1310delTAGA; p.Ile436fs), and (NM_015125:c.4421T>G; p.Val1474Gly). All but 2 of these 80 variants were also present in xenograft, along with 7 new variants. Deep sequencing of the 87 SNVs and InDels in the original tumor (WHO grade III, primary O) and in a second-generation xenograft (xenograft) revealed that only 11 variants, including (NM_005896:c.395G>A; p. Arg132His), (NM_006742.2:c.650G>A; p.Arg217Gln), and (NM_001256188:c.470G>A; p.Arg157His), along with a variant in the promoter (C250T, NM_198253.2: c.-146G>A), were already present in primary O. Allele frequencies of the 11 variants were calculated to assess their potential as putative driver genes. A missense change in (NM_022569:c.2392C>G; p.Leu798Val) on 4q exhibited an increasing allele frequency (~ 20%, primary O, 80%, recurrent O and 100%, xenograft), consistent with a selection event. Sequencing of in a cohort of 15 oligodendrogliomas, however, revealed no additional cases with potential protein disrupting variants. Our analysis illuminated a tumor evolutionary series of events, which included 1p/19q codeletion, R132H, and C250T as early events, followed by loss of function of and mutations in and as late events.
我们之前报道了源自伴有1p/19q共缺失的复发性少突胶质细胞瘤的一种罕见异种移植模型的建立。在此，我们详细分析了来自复发性少突胶质细胞瘤（世界卫生组织III级，复发性O）和第一代异种移植瘤（异种移植瘤）的外显子组测序数据集。复发性O中在蛋白质水平具有潜在影响的体细胞单核苷酸变异（SNV）和小插入缺失（= 80）包括 （NM_005896:c.395G>A；p.Arg132His）、 （NM_003902:c.1307_1310delTAGA；p.Ile436fs）和 （NM_015125:c.4421T>G；p.Val1474Gly）中的变异。这80个变异中除2个外，其余在异种移植瘤中也存在，同时还有7个新变异。对原发肿瘤（世界卫生组织III级，原发性O）和第二代异种移植瘤（异种移植瘤）中的87个SNV和插入缺失进行深度测序发现，只有11个变异，包括 （NM_005896:c.395G>A；p.Arg132His）、 （NM_006742.2:c.650G>A；p.Arg217Gln）和 （NM_001256188:c.470G>A；p.Arg157His），以及 启动子中的一个变异（C250T，NM_198253.2:c.-146G>A），在原发性O中已经存在。计算这11个变异的等位基因频率以评估它们作为假定驱动基因的可能性。4号染色体上 （NM_022569:c.2392C>G；p.Leu798Val）的一个错义改变表现出等位基因频率增加（~ 20%，原发性O；80%，复发性O；100%，异种移植瘤），这与一个选择事件一致。然而，对15例少突胶质细胞瘤队列中的 进行测序，未发现其他具有潜在蛋白质破坏变异的病例。我们的分析揭示了一个肿瘤进化系列事件，其中包括1p/19q共缺失、 R132H和 C250T作为早期事件，随后是 功能丧失以及 和 中的突变作为晚期事件。
