TERT structural rearrangements in metastatic pheochromocytomas
TERT structural rearrangements in metastatic pheochromocytomas
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DOI：
10.1530/erc-17-0306
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发表时间：
2018-01-01
影响因子：
3.9
通讯作者：
Tothill, Richard W.
中科院分区：
文献类型：
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作者：
Dwight, Trisha;Flynn, Aidan;Tothill, Richard W.
嗜铬细胞瘤（PC）和副神经节瘤（PGL）是内分泌肿瘤，其转移进展的遗传和临床病理学特征仍不完全清楚。因此，无法预测原发性肿瘤转移的风险。早期诊断个体发展转移的高风险在临床上是重要的，并且鉴定预测转移潜能的新生物标志物具有高价值。TERT的激活与许多恶性肿瘤相关，包括PC/PGL。然而，大多数PC/PGL中的TERT激活机制仍不清楚。由于PC/PGL中很少发生TERT启动子突变，我们假设其他机制-如结构变异-可能是这些肿瘤中TERT激活的基础。从35例PC和4例PGL中，我们确定了3例原发性PC发生转移并伴有TERT表达升高，每例均缺乏TERT启动子突变和启动子DNA甲基化。使用全基因组测序，我们确定了其中两个肿瘤中TERT基因座附近的体细胞结构改变。在这两种肿瘤中，基因组重排导致超级增强子定位在靠近TERT启动子的位置，这可能是嗜铬细胞中正常情况下受到严格抑制的TERT表达被激活的原因
Pheochromocytomas (PC) and paragangliomas (PGL) are endocrine tumors for which the genetic and clinicopathological features of metastatic progression remain incompletely understood. As a result, the risk of metastasis from a primary tumor cannot be predicted. Early diagnosis of individuals at high risk of developing metastases is clinically important and the identification of new biomarkers that are predictive of metastatic potential is of high value. Activation of TERT has been associated with a number of malignant tumors, including PC/PGL. However, the mechanism of TERT activation in the majority of PC/PGL remains unclear. As TERT promoter mutations occur rarely in PC/PGL, we hypothesized that other mechanisms - such as structural variations - may underlie TERT activation in these tumors. From 35 PC and four PGL, we identified three primary PCs that developed metastases with elevated TERT expression, each of which lacked TERT promoter mutations and promoter DNA methylation. Using whole genome sequencing, we identified somatic structural alterations proximal to the TERT locus in two of these tumors. In both tumors, the genomic rearrangements led to the positioning of super-enhancers proximal to the TERT promoter, that are likely responsible for the activation of the normally tightly repressed TERT expression in chromaffin cells