Genetic and epigenetic stability of oligodendrogliomas at recurrence.
Genetic and epigenetic stability of oligodendrogliomas at recurrence.
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DOI：
10.1186/s40478-017-0422-z
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发表时间：
2017-03-07
影响因子：
7.1
通讯作者：
Saito N
中科院分区：
文献类型：
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作者：
Aihara K;Mukasa A;Nagae G;Nomura M;Yamamoto S;Ueda H;Tatsuno K;Shibahara J;Takahashi M;Momose T;Tanaka S;Takayanagi S;Yanagisawa S;Nejo T;Takahashi S;Omata M;Otani R;Saito K;Narita Y;Nagane M;Nishikawa R;Ueki K;Aburatani H;Saito N
在弥漫性胶质瘤中，少突胶质细胞瘤的预后相对较好，对放疗和化疗反应良好，很少进展为非常侵袭性的肿瘤。为了阐明这种行为和肿瘤复发过程中肿瘤演变的遗传和表观遗传背景，我们比较分析了12对1 p/19 q共缺失的原发性和复发性少突胶质细胞瘤。这些患者的初始治疗主要是单纯化疗。替莫唑胺3例，甲基苄肼、尼莫司汀、长春新碱（PAV化疗）7例。复发时WHO组织学分级基本稳定，2例升高，9例相同，1例降低。全外显子组测序结果表明，原发性和复发性肿瘤之间的共享突变率相对较低，范围为3.2-57.9%（平均33.3%），表明分支进化模式。在整个病程中存在的躯干改变仅限于IDH 1突变、1 p/19 q共缺失和TERT启动子突变，并且在原发性和复发性肿瘤之间未一致地观察到已知候选肿瘤抑制基因CIC和FUBP 1的突变。肿瘤内不同区域的多个样本显示出明显的肿瘤内异质性。值得注意的是，一般来说，复发后突变的数量没有显著差异，保持在100以下，并且没有观察到超变表型。FUBP 1突变、9 p21缺失和TCF 12突变是复发时发现的少数复发性新发改变，表明这些事件在复发时被克隆选择，但不足以增强恶性程度。通过Illumina 450 K阵列测量的全基因组甲基化状态在复发和原发肿瘤之间是稳定的。总之，尽管少突胶质细胞瘤显示出明显的突变异质性，但在复发时未观察到组织学恶性转化伴随事件，如突变数量的显著增加和表观遗传特征的变化，表明少突胶质细胞瘤中明显的时间和空间遗传异质性不会导致肿瘤快速进展。本文的在线版本（doi：10.1186/s40478-017-0422-z）包含补充材料，可供授权用户使用。
Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression. The online version of this article (doi:10.1186/s40478-017-0422-z) contains supplementary material, which is available to authorized users.