Li Xiaolei, Zhang Yan, Zhao Luyang, Wang Lingxiong, Wu Zhiqiang, Mei Qian, Nie Jing, Li Xiang, Li Yali, Fu Xiaobing, Wang Xiaoning, Meng Yuanguang, Han Weidong
Department of Molecular Biology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing, China.
Department of Bio-therapeutic, Chinese PLA General Hospital, Beijing, China.
Hum Mol Genet. 2014 Nov 15;23(22):6008-21. doi: 10.1093/hmg/ddu330. Epub 2014 Jun 26.
Endometriosis is a complex and enigmatic disease that arises from the interplay among multiple genetic and environmental factors. The defining feature of endometriosis is the deposition and growth of endometrial tissues at sites outside of the uterine cavity. Studies to date have established that endometriosis is heritable but have not addressed the causal genetic variants for this disease. Here, we conducted whole-exome sequencing to comprehensively search for somatic mutations in both eutopic and ectopic endometrium from 16 endometriosis patients and five normal control patients using laser capture microdissection. We compared the mutational landscape of ectopic endometrium with the corresponding eutopic sample from endometriosis patients compared with endometrium from normal women and identified previously unreported mutated genes and pathway alternations. Statistical analysis of exome data identified that most genes were specifically mutated in both eutopic and ectopic endometrium cells. In particular, genes that are involved in biological adhesion, cell-cell junctions, and chromatin-remodeling complex(es) were identified, which partially supports the retrograde menstruation theory that proposes that endometrial cells are refluxed through the fallopian tubes during menstruation and implanted onto the peritoneum or pelvic organs. Conspicuously, when we compared exomic mutation data for paired eutopic and ectopic endometrium, we identified a mutational signature in both endometrial types for which no overlap in somatic single nucleotide variants were observed. These mutations occurred in a mutually exclusive manner, likely because of the discrepancy in endometriosis pathology and physiology, as eutopic endometrium rapidly regrows, and ectopic endometrial growth is inert. Our findings provide, to our knowledge, an unbiased view of the landscape of genetic alterations in endometriosis and vital information for indicating that genetic alterations in cytoskeletal and chromatin-remodeling proteins could be involved in the pathogenesis of endometriosis, thus implicating a novel therapeutic possibility for endometriosis.
子宫内膜异位症是一种复杂且神秘的疾病，由多种遗传和环境因素相互作用引起。子宫内膜异位症的决定性特征是子宫内膜组织在子宫腔外部位的沉积和生长。迄今为止的研究已证实子宫内膜异位症具有遗传性，但尚未确定该疾病的致病基因变异。在此，我们进行了全外显子组测序，以使用激光捕获显微切割技术全面搜索16例子宫内膜异位症患者和5例正常对照患者的在位内膜和异位内膜中的体细胞突变。我们将异位内膜的突变图谱与子宫内膜异位症患者相应的在位样本进行比较，并与正常女性的子宫内膜进行比较，从而鉴定出先前未报道的突变基因和通路改变。外显子组数据的统计分析表明，大多数基因在在位内膜细胞和异位内膜细胞中均发生特异性突变。特别是，鉴定出了参与生物黏附、细胞间连接和染色质重塑复合体的基因，这部分支持了逆行月经理论，该理论认为子宫内膜细胞在月经期间通过输卵管反流并植入腹膜或盆腔器官。值得注意的是，当我们比较配对的在位内膜和异位内膜的外显子组突变数据时，我们在两种内膜类型中均鉴定出一种突变特征，在体细胞单核苷酸变异中未观察到重叠。这些突变以互斥的方式发生，可能是由于子宫内膜异位症病理生理学的差异，因为在位内膜迅速再生，而异位内膜生长不活跃。据我们所知，我们的研究结果提供了对子宫内膜异位症遗传改变图谱的无偏见解，并提供了重要信息，表明细胞骨架和染色质重塑蛋白的遗传改变可能参与子宫内膜异位症的发病机制，从而暗示了子宫内膜异位症的一种新的治疗可能性。
