由于症状性子宫肌瘤引起的重复干预的临床和分子风险因素

子宫肌瘤的复发甚至再次干预在肌瘤切除术后较为常见。关于与重复干预相关的因素知之甚少。本研究旨在确定首次腹腔镜或开腹肌瘤切除术后与肌瘤相关的再干预的发生频率，并分析临床和分子风险因素。另一个目标是界定来自重复手术的克隆相关肿瘤的频率。本回顾性队列研究纳入了2009至2014年接受腹腔镜或开腹肌瘤切除术的234名女性。通过医疗记录收集关于重复肌瘤相关干预以及其他临床因素的信息，随访中位时间为11.4年（范围7.9-13.8年）。采用Kaplan-Meier估计和Cox比例风险模型分析临床风险因素对再干预风险的影响。分子分析方面，我们检测了33名多次手术患者的133个福尔马酰辅酶水固定石蜡包埋肌瘤样本的突变谱。通过Sanger测序和免疫组化筛查三种主要肌瘤驱动变异——介导复合物亚基12突变、高迁移率族AT-hook 2过表达及延胡索酸水合酶缺乏——以筛查肿瘤。为了进一步评估肿瘤的克隆关系，我们对21名患者的52个肌瘤进行了全外显子测序，这些患者在多次手术中获得的肿瘤中表现出相同的驱动突变。肌瘤切除术后11.4年再干预率为20%（46/234）。首次肌瘤切除术时切除的肌瘤数量是一个风险因素（风险比1.21；95%置信区间1.09-1.34）。首次肌瘤切除术年龄（风险比0.94；95%置信区间0.89-0.99）和术后孕次（风险比0.23；95%置信区间0.09-0.60）是保护因素。对首次和非首次手术的肿瘤的分子表征确认，33名患者中的3名（9%）的肿瘤具有克隆关系。未发现携带介导复合物亚基12突变（最常见的肌瘤驱动突变）的肌瘤具有克隆关系。在33名患者的复发肌瘤中检测到延胡索酸水合酶缺乏，全部携带胚系延胡索酸水合酶突变，这是遗传性肌瘤样病变与肾细胞癌综合征的特征。最后，发现3名（9%）患者在两个肿瘤中都表现出新近鉴定的肌瘤驱动基因——YEATS结构域蛋白4的体细胞突变，且所有YEATS蛋白4突变各不相同，因此肿瘤之间非克隆关系。我们的研究显示，肌瘤切除术后再次干预较为常见。子宫肌瘤通常独立发生，但部分具有克隆起源。重复肌瘤的发生可能与遗传易感性有关，比如胚系延胡索酸水合酶突变。来自同一患者多个肌瘤中鉴定出的不同体细胞突变（如YEATS结构域蛋白4）提示该蛋白在重复肌瘤中的潜在作用。

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.