Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report
Expression of unfolded protein response markers in the pheochromocytoma with Waardenburg syndrome: a case report
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DOI：
10.1186/s12902-020-00574-9
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发表时间：
2020-06-22
影响因子：
2.7
通讯作者：
Akamizu, Takashi
中科院分区：
文献类型：
--
作者：
Morita, Shuhei;Takeshima, Ken;Akamizu, Takashi
背景：进一步了解内分泌肿瘤的发病机制，提出内分泌肿瘤的治疗策略已迫在眉睫。大量具有致癌作用的分泌蛋白被认为在内分泌肿瘤中诱导内质网未折叠蛋白反应，但其证据有限。病例介绍一位40岁女性有大约10年的间歇性头痛病史。在CT扫描发现右侧肾上腺有肿块后，她住进了我们医院。她被诊断为1型瓦登堡综合征，症状为角质障碍、蓝色虹膜和左侧感觉神经性听力损失。尿儿茶酚胺水平明显升高。I-123-MIBG核素扫描显示她的肾上腺摄取了肿块。肾上腺切除后，头痛消失，尿儿茶酚胺水平在2周内降至正常范围。基因组测序发现HER嗜铬细胞瘤中转录因子PAX3基因c.A175T(p.Ile59Phe)发生胚系突变，原癌基因Ret(p.Asp631_Leu633delinsGlu)出现新的体细胞突变c.1893_1898del(p.Asp631_Leu633delinsGlu)。她的嗜铬细胞瘤中RET的RNA表达水平是正常肾上腺的139倍。未折叠蛋白反应标记物Bip/GRP78、CHOP、ATF4和ATF6在嗜铬细胞瘤中的表达也增加。结论我们报告一例罕见的嗜铬细胞瘤合并1型Waardenburg综合征。这是首例发现RET基因新的体细胞突变的嗜铬细胞瘤中未折叠蛋白反应被激活的病例。我们的发现可能支持在内分泌肿瘤中激活未折叠蛋白反应，这可能是一个潜在的治疗靶点。
Background It is clinically emergent to further understand the pathological mechanism to advance therapeutic strategy for endocrine tumors. A high amount of secretory protein with tumorigenic triggers are thought to induce unfolded protein response in endoplasmic reticulum in endocrine tumors, but its evidence is limited. Case presentation A 40-year-old woman had an approximately 10-year history of intermittent headaches. After the incidental detection of a mass in her right adrenal gland by CT scan, she was admitted to our hospital. She had been diagnosed as type 1 Waardenburg syndrome with the symptoms of dystopia canthorum, blue iris, and left sensorineural hearing loss. Urinary catecholamine levels were markedly elevated.I-123-MIBG scintigraphy showed uptake in the mass in her adrenal gland. After the adrenalectomy, her headaches disappeared and urinary catecholamine levels decreased to normal range within 2 weeks. Genome sequencing revealed germline mutation of c.A175T (p.Ile59Phe) in transcription factor PAX3 gene and somatic novel mutation of c.1893_1898del (p. Asp631_Leu633delinsGlu) in proto-oncogene RET in her pheochromocytoma. RNA expression levels of RET were increased 139 times in her pheochromocytoma compared with her normal adrenal gland. Those of unfolded protein response markers, Bip/GRP78, CHOP, ATF4, and ATF6, were also increased in the pheochromocytoma. Conclusion We report a rare case of pheochromocytoma with type 1 Waardenburg syndrome. This is the first case to show the activation of unfolded protein response in the pheochromocytoma with the novel somatic mutation in RET gene. Our findings may support that unfolded protein response is activated in endocrine tumors, which potentially could be a candidate of therapeutic target.