由于有症状的子宫平滑肌瘤，重复干预措施的临床和分子危险因素

肌瘤切除术后重复平滑肌瘤发生甚至重新干预是常见的。对重复干预措施有关的因素知之甚少。该研究旨在确定最初的腹腔镜或腹部肌瘤切除术后与平滑肌相关的重新干预的频率，并分析重新中间的临床和分子风险因素。另一个目的是定义重复手术中克隆相关肿瘤的频率。这项回顾性的队列研究包括2009年至2014年在2009年至2014年进行腹腔镜或腹部肌瘤切除术的234名妇女。有关重复平滑肌相关的干预措施的信息。在Median Plastian Plastian Plastical Clanike Clandial Clanike and Median Plastect in Median Tasterex of 11.4年度（范围内）（范围为7.4年）。 Kaplan-Meier估计量和COX比例危害模型分析了临床风险因素对重新干预风险的影响。对于分子分析，我们检查了来自33例重复手术患者的133种福尔马林固定石蜡膜样品样品的突变谱。我们筛选了3个原发性平滑肌驱动器驱动器改变剂复合物亚基12突变，高迁移率组AT-HOK 2过表达以及富马酸氢酸氢化氢酯酶缺陷量化的Sanger测序和免疫组织化学的肿瘤。为了进一步评估肿瘤的克隆关系，我们对21例表现出从多种过程获得的肿瘤改变相同驱动因素改变的患者进行了52例平滑肌瘤的全异位测序。进行肌瘤切除术后11。4年的重新介入率为20％（46/234）。在指数肌瘤切除术时去除的平滑肌瘤数量是危险因素（危险比1.21; 95％置信区间1.09-1.34）。指数肌瘤切除术的年龄（危险比0.94; 95％置信区间0.89-0.99）和术后均等（危险比0.23; 95％置信区间0.09-0.60）是保护因素。来自指数和非指数操作的肿瘤的分子表征证实了3/33（9％）患者的肿瘤的克隆关系。没有一个具有介体复合体亚基12突变的平滑肌瘤 - 最常见的平滑肌驱动器驱动器与克隆相关。在3/33（9％）患者的重复平滑肌瘤中检测到富马酸盐水合物缺陷。所有这些患者都有一种种系富马酸盐水合物突变，这对于遗传性平滑肌瘤病和肾细胞癌综合征是独特的。最后，我们确定了3例（3/33; 9％）患者2例肿瘤，每个肿瘤在最近确定的新型平滑肌瘤驱动基因，含有Yeats结构域的蛋白质4中显示体突变。所有含有yeats域蛋白4突变的蛋白质4突变都是不同的，因此肿瘤并不具有金属相关性。子宫平滑肌瘤通常独立发展，但有些具有克隆起源。重复平滑肌瘤的发生可能是由于遗传易感性引起的，例如种系富马酸盐水合物突变。来自同一患者的多个平滑肌瘤中鉴定出的含有域的含有域蛋白4突变的明显的体细胞叶状蛋白4表明，在重复平滑肌瘤中含有叶芝域的蛋白4的可能作用。

Repeat leiomyoma occurrence or even reintervention is common after myomectomy. Little is known about the factors related to repeat interventions.This study aimed to determine the frequency of leiomyoma-related reintervention after an initial laparoscopic or abdominal myomectomy and to analyze both clinical and molecular risk factors for reinterventions. Another objective was to define the frequency of clonally related tumors from repeat operations.This retrospective cohort study included 234 women who had undergone laparoscopic or abdominal myomectomy in 2009 to 2014. Information on repeat leiomyoma-related interventions as well as on other clinical factors was collected from medical records after a median follow-up time of 11.4 years (range 7.9-13.8 years) after the index procedure. The effect of clinical risk factors on the risk of reintervention was analyzed by the Kaplan-Meier estimator and the Cox proportional hazards model. For molecular analyses, we examined the mutation profiles of 133 formalin-fixed paraffin-embedded leiomyoma samples from 33 patients with repeat operations. We screened the tumors for the 3 primary leiomyoma driver alterations-mediator complex subunit 12 mutations, high mobility group AT-hook 2 overexpression, and fumarate hydratase-deficiency-utilizing Sanger sequencing and immunohistochemistry. To further assess the clonal relationship of the tumors, we executed whole-exome sequencing for 52 leiomyomas from 21 patients who exhibited the same driver alteration in tumors obtained from multiple procedures.Reintervention rate at 11.4 years after myomectomy was 20% (46/234). Number of leiomyomas removed at the index myomectomy was a risk factor (hazard ratio 1.21; 95% confidence interval 1.09-1.34). Age at index myomectomy (hazard ratio 0.94; 95% confidence interval 0.89-0.99) and postoperative parity (hazard ratio 0.23; 95% confidence interval 0.09-0.60) were protective factors. Molecular characterization of tumors from index and nonindex operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a mediator complex subunit 12 mutation-the most common leiomyoma driver-were confirmed clonally related. Fumarate hydratase-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline fumarate hydratase mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer syndrome. Finally, we identified 3 (3/33; 9%) patients with 2 tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS domain-containing protein 4. All YEATS domain-containing protein 4 mutations were different and thus the tumors were not clonally related.Our study shows that reintervention is common after surgical myomectomy. Uterine leiomyomas typically develop independently, but some share a clonal origin. Repeat leiomyoma occurrence may be due to genetic predisposition, such as a germline fumarate hydratase mutation. Distinct somatic YEATS domain-containing protein 4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS domain-containing protein 4 in repeat leiomyomas.