垂体促肾上腺皮质激素腺瘤全基因组测序分析

发布时间：2018-04-14 02:16

本文选题：垂体腺瘤 + ACTH　；参考：《浙江大学》2015年博士论文

【摘要】：研究目的：垂体促肾上腺皮质激素(adrenocorticotrophic hormone, ACTH)腺瘤是一种常见的垂体腺瘤,由于ACTH的过度分泌,导致人体内皮质醇代谢异常,表现出向心性肥胖、血糖血脂代谢异常等临床症状。本研究的目的是为垂体促肾上腺皮质激素腺瘤发病的分子机制提供更多基因组水平的数据和结果。研究方法：本研究对9名确诊为垂体ACTH腺瘤并经过手术治疗的患者的垂体瘤组织标本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、结构变异的分析与验证。所得热点突变结果在39例后续的垂体ACTH腺瘤组织样本中进行验证。研究结果：在测序质量、数据量、深度和覆盖度良好的前提下,主要实验结果如下：单核苷酸突变、小的插入或缺失分析结果显示24例患者垂体瘤标本中发现USP8基因热点突变,突变类型可分成6类,突变率为50.0%；1例先证肿瘤样本中发现USP8拷贝数增加；USP8突变组患者的治疗前血浆ACTH水平高于USP8野生组患者激素水平,但未达到统计学显著；先证肿瘤样本中2例存在抑癌基因突变,突变基因为ATR、TP53、KMT2C及NF1。拷贝数变异分析结果显示先证肿瘤样本中1例垂体瘤样本中存在多条染色体的整条丢失。结构变异的分析发现先证肿瘤样本中存在意义未明的结构变异。而先证肿瘤样本中,有2例样本尚未发现任何可能导致垂体瘤发生的基因变异。在胚系突变的检测中,本研究未发现基因突变。研究结论：本研究对垂体ACTH腺瘤组织的全基因组扫描和测序分析结果验证了近期文献报道的USP8基因热点突变存在于约半数的垂体ACTH腺瘤样本中；首次发现垂体腺瘤样本中存在USP8的拷贝数增加,可能是导致垂体ACTH瘤发生的分子机制之一；能够引起AC发现了垂体ACTH瘤组织中抑癌基因单核苷酸变异以及染色体丢失情况,即可能存在另一种包含抑癌基因突变和染色体变异的垂体ACTH瘤发生机制；此外,尚有部分患者的肿瘤组织中未发现任何基因变异,推测变异可能发生在其他组学水平。本研究在垂体ACTH腺瘤患者中尚未检测到胚系突变。
[Abstract]:Objective: adrenocorticotropic hormone adrenocorticotrophic hormone (ACTH) adenoma is a common pituitary adenoma. The hypersecretion of ACTH leads to abnormal metabolism of cortisol in human body, which is characterized by concentric obesity and abnormal metabolism of blood glucose and lipids.The aim of this study is to provide more genome-level data and results for the molecular mechanism of pituitary adrenocorticotropic hormone adenoma.Methods: in this study, the whole genome of 9 patients with pituitary ACTH adenoma and matched peripheral blood samples were sequenced and single nucleotide mutations, small insertions or deletions were performed.Analysis and verification of copy number variation and structural variation.The results of hot spot mutation were verified in 39 subsequent pituitary ACTH adenoma tissue samples.Results: on the premise of good sequencing quality, data volume, depth and coverage, the main results were as follows: single nucleotide mutation, small insertion or deletion analysis showed that hot spot mutations of USP8 gene were found in 24 patients with pituitary adenoma.The mutation type can be divided into 6 types. The mutation rate of 50. 0% was 50. 0%. The plasma ACTH level of the patients with increased copy number of USP8 was higher than that of the wild patients with USP8 before treatment, but it was not statistically significant.Tumor suppressor gene mutation was found in 2 cases, which were caused by ATR TP53 KMT2C and NF1.The results of copy number variation analysis showed that there was a complete loss of multiple chromosomes in one pituitary tumor sample.Structural variation analysis showed that there were unknown structural variations in tumor samples.However, 2 of the patients with primary tumor had not found any genetic variation that might lead to pituitary adenoma.No gene mutation was found in the detection of blastocyst mutations.Conclusion: the results of genomic scanning and sequencing of pituitary ACTH adenoma confirmed that the hot spot mutations of USP8 gene were found in about half of the samples of pituitary ACTH adenoma.The increase of USP8 copy number in pituitary adenoma samples was first found, which may be one of the molecular mechanisms leading to the occurrence of pituitary ACTH tumor, and can cause the single nucleotide variation of tumor suppressor gene and chromosome loss in pituitary ACTH tumor.That is to say, there may be another mechanism of pituitary ACTH tumorigenesis including tumor suppressor gene mutation and chromosome variation. In addition, no gene mutation has been found in the tumor tissues of some patients, which suggests that the mutation may occur at other levels.In this study, no embryonal mutation was detected in patients with pituitary ACTH adenoma.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R736.4

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