Driver mutations in ADGRL3 are involved in the evolution of ependymoma
Driver mutations in ADGRL3 are involved in the evolution of ependymoma
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ADGRL3 的驱动突变参与室管膜瘤的进化
DOI：
10.1038/s41374-021-00721-3
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发表时间：
2022-01
影响因子：
5
通讯作者：
Fang Wang
中科院分区：
文献类型：
--
作者：
Jing Wang;Shao-yan Xi;Qi Zhao;Yun-fei Xia;Qun-ying Yang;Hai-ping Cai;Fang Wang
虽然最近在室管膜瘤的分子病理学方面取得了进展，但对其发展过程中潜在的分子进化知之甚少。在这里，我们评估了一名9岁的幕上室管膜瘤患者的临床、病理和分子进化过程，该患者曾7次复发幕上室管膜瘤，并于19岁时死于颅内多区域复发。研究人员对7个肿瘤样本（1个原发肿瘤和6个复发肿瘤）进行了全基因组测序（WGS），以阐明突变景观并确定肿瘤进化的潜在驱动突变。7个肿瘤标本的遗传谱显示出显著的异质性，表明其具有高度分支的进化模式。突变特征和染色体分裂随治疗而改变。引人注目的是，粘附G蛋白偶联受体L3 （ADGRL3，也称为嗜Latrophilins 3， LPNH3）在整个疾病过程中被发现持续突变。然而，在我院接受手术的其他78例室管膜瘤患者的Sanger测序未发现本病例中发现的ADGRL3基因改变。与正常脑组织（n= 3）相比，室管膜瘤（n= 36）中ADGRL3 mRNA水平显著降低。III级室管膜瘤中ADGRL3表达最低。此外，ADGRL3 mRNA水平较低的室管膜瘤总生存期较短。因此，我们的研究结果证明了一个罕见的涉及ADGRL3的室管膜瘤的进化过程。
Although there have been recent advances in the molecular pathology of ependymomas, little is known about the underlying molecular evolution during its development. Here, we assessed the clinical, pathological and molecular evolutionary process of ependymoma recurrence in a 9-year-old patient who had seven recurrences of supratentorial ependymoma and died from intracranial multiregional recurrences at the age of 19 years old. Whole-genome sequencing (WGS) of 7 tumor samples (1 primary and 6 subsequent recurrent tumors) was performed to elucidate the mutation landscape and identify potential driver mutations for tumor evolution. The genetic profiles of the seven tumor specimens showed significant heterogeneity and suggested a highly branched evolutionary pattern. The mutational signatures and chromothripsis changed with treatments. Strikingly, adhesion G protein-coupled receptor L3 (ADGRL3, also known as Latrophilins 3, LPNH3) was found to be consistently mutated during the entire disease process. However, Sanger sequencing of other 78 ependymoma patients who underwent surgery at our institution showed no genetic alteration of ADGRL3, as found in the present case. The mRNA levels of ADGRL3 were significantly lower in ependymomas (n= 36), as compared with normal brain tissue (n= 3). Grade III ependymomas had the lowest ADGRL3 expression. Moreover, ependymomas with lower mRNA level of ADGRL3 had shorter overall survival. Our findings, therefore, demonstrate a rare evolutionary process of ependymoma involving ADGRL3.
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