垂体促肾上腺皮质激素腺瘤基因型与临床表型的相关性研究  

Genotype-phenotype landscape of pituitary adrenocorticotroph hormone adenoma

作　　者：苗卉 王珞 龚凤英 段炼 王林杰 姚勇[2] 冯铭[2] 邓侃[2] 王任直[2] 管彦芳 朱惠娟 卢琳 Miao Hui;Wang Luo;Gong Fengying;Duan Lian;Wang Linjie;Yao Yong;Feng Ming;Deng Kan;Wang Renzhi;Guan Yanfang;Zhu Huijuan;Lu Lin(Key Laboratory of Endocrinology of National Health Commission,Department of Endocrinology,Translational Medicine Center,State Key Laboratory of Complex Severe and Rare Diseases,were collected inPeking Union Medical College Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100730,China;Department of Neurosurgery,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100730,China;GenePlus-Beijing,Beijing 102206,China)

机构地区：[1]中国医学科学院,北京协和医学院,北京协和医院内分泌科,卫健委内分泌重点实验室,疑难重症及罕见病国家重点实验室,协和转化医学中心,100730 [2]中国医学科学院,北京协和医学院,北京协和医院神经外科,100730 [3]北京吉因加医学检验实验室有限公司,102206

出　　处：《中华内分泌代谢杂志》2022年第2期125-131,共7页Chinese Journal of Endocrinology and Metabolism

基　　金：国家重点研发计划(2016YFC0901501)。

摘　　要：目的库欣病(Cushing′s disease,CD)是由于垂体促肾上腺皮质激素(adrenocorticotroph hormone,ACTH)腺瘤分泌过多促肾上腺皮质激素,引起血浆皮质醇水平升高,导致血糖血脂代谢异常等一系列病理生理变化。若得不到有效治疗,病死率较高,因此阐明库欣病的发病机制十分重要。本研究旨在利用全基因组测序技术探索垂体ACTH腺瘤的发病机制。方法选取9例确诊为垂体ACTH腺瘤并经过手术治疗患者的垂体瘤组织和与之配对的外周血样本进行了全基因组测序,并进行单核苷酸突变、小的插入或缺失、拷贝数变异、染色体结构变异的分析与验证。结果5例患者发现USP8基因体细胞热点突变(p.Ser718del、p.Ser718Pro、p.Pro720Arg、p.Pro720Gln),突变率为55.6%;1例患者检测出USP8拷贝数增加;1例USP8野生型患者检测出TP53(p.Cys135Tyr)、NF1(p.Val1049Glufs*11)及KMT2C(c.3323+1G>A)突变。拷贝数变异分析结果显示1例USP8野生型患者存在多条染色体的杂合性缺失。结构变异分析发现2例意义未明的结构变异。本研究未发现胚系基因突变。结论USP8基因的体细胞突变和拷贝数增加、TP53等肿瘤相关基因的突变、广泛的体细胞拷贝数变异共同参与垂体ACTH腺瘤的致病。染色体结构变异可能有助于识别高危垂体ACTH腺瘤,患者需要更密切的随访和更积极的治疗。Objective Cushing′s disease(CD)is caused by the pituitary adrenocorticotroph hormone(ACTH)secreting adenomas,leading to increased serum cortisol levels and various abnormal metabolic processes.Untreated CD is linked to high mortality,thus it is critical to elucidate its pathogenesis.This study aims to explore the pathogenesis of pituitary ACTH adenomas using whole-genome sequencing analysis.Methods Fresh tumor tissues and peripheral blood samples were collected in 9 confirmed cases of pituitary ACTH adenomas who underwent surgery.Whole genome sequencing was then performed,followed by analysis and verification of single nucleotide mutations,copy number variation(CNV)and chromosome structure variations.Results Somatic USP8 mutations(p.Ser718del,p.Ser718Pro,p.Pro720Arg,p.Pro720Gln)were found in 5 patients,with a rate of 55.6%;CNV of USP8 was detected in 1 patient;TP53(p.Cys135Tyr),NF1(p.Val1049Glufs*11)and KMT2C(c.3323+1G>A)mutations were identified in 1 patient harboring wild-type USP8.CNV analysis showed a loss of heterozygosity in multiple chromosomes in a wild-type USP8 patient.Structural variations were found in 2 with unknown significance.No germline gene mutations were detected in this study.Conclusion Somatic USP8 mutations,increased copy number of USP8,variations of tumor-related genes such as TP53 and extensive somatic CNV all contribute to pathogenesis of CD.Chromosomal structure variations may suggest high-risk pituitary ACTH adenomas,and call for frequent follow-up and aggressive treatment.

关 键 词：垂体腺瘤 ACTH 全基因组测序 USP8 

分 类 号：R736.4[医药卫生—肿瘤]