子宫肌瘤切除术后，肌瘤重复发生甚至重新干预是很常见的。对于与重复干预相关的因素知之甚少。本研究旨在确定初次腹腔镜或腹部子宫肌瘤切除术后与肌瘤相关的再次干预的频率，并分析再次干预的临床和分子危险因素。另一个目标是确定重复手术中克隆相关肿瘤的发生率。这项回顾性队列研究纳入了 2009 年至 2014 年接受过腹腔镜或腹部子宫肌瘤切除术的 234 名女性。在索引手术后中位随访时间为 11.4 年（范围 7.9-13.8 年）后，从医疗记录中收集有关重复子宫肌瘤相关干预措施以及其他临床因素的信息。通过Kaplan-Meier估计量和Cox比例风险模型分析临床危险因素对再干预风险的影响。为了进行分子分析，我们检查了来自 33 名重复手术患者的 133 份福尔马林固定石蜡包埋的平滑肌瘤样本的突变谱。我们利用 Sanger 测序和免疫组织化学筛选了肿瘤的三种原发性平滑肌瘤驱动基因改变——MED12 突变、HMGA2 过表达和 FH 缺陷。为了进一步评估肿瘤的克隆关系，我们对来自 21 名患者的 52 例平滑肌瘤进行了全外显子组测序，这些患者在多次手术中获得的肿瘤中表现出相同的驱动改变。子宫肌瘤切除术后 11.4 年的再干预率为 20%（46/ 234）。在指数子宫肌瘤切除术中切除的子宫肌瘤数量是一个危险因素（风险比 1.21；95% 置信区间 1.09-1.34）。首次子宫肌瘤切除术时的年龄（风险比 0.94；95% 置信区间 0.89-0.99）和术后产次（风险比 0.23；95% 置信区间 0.09-0.60）是保护因素。来自指标和非指标手术的肿瘤的分子特征证实了 3/33 (9%) 患者的肿瘤的克隆关系。没有一个含有 MED12 突变（最常见的平滑肌瘤驱动因素）的平滑肌瘤被证实与克隆相关。在 3/33 (9%) 患者的重复肌瘤中检测到 FH 缺陷。所有这些患者都携带种系 FH 突变，这是遗传性平滑肌瘤病和肾细胞癌 (HLRCC) 综合征的特征。最后，我们确定了三名（3/33；9%）患有两个肿瘤的患者，每个患者在最近发现的新型平滑肌瘤驱动基因 YEATS4 中都表现出体细胞突变。所有 YEATS4 突变均不同，因此肿瘤不存在克隆相关性。我们的研究表明，子宫肌瘤切除术后再次干预很常见。子宫肌瘤通常独立发育，但有些具有克隆起源。平滑肌瘤的重复发生可能是由于遗传倾向，例如种系 FH 突变。在同一患者的多个平滑肌瘤中发现的独特体细胞 YEATS4 突变表明 YEATS4 在重复性平滑肌瘤中可能发挥作用。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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 2009-2014. 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 three primary leiomyoma driver alterations-MED12 mutations, HMGA2 overexpression, and FH-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 non-index operations confirmed a clonal relationship of the tumors in 3/33 (9%) patients. None of the leiomyomas harboring a MED12 mutation -the most common leiomyoma driver- were confirmed clonally related. FH-deficiency was detected in repeat leiomyomas from 3/33 (9%) patients. All these patients harbored a germline FH mutation, which is distinctive for the hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. Finally, we identified three (3/33; 9%) patients with two tumors each displaying somatic mutations in a recently identified novel leiomyoma driver gene, YEATS4. All YEATS4 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 FH mutation. Distinct somatic YEATS4 mutations identified in multiple leiomyomas from the same patient indicate a possible role for YEATS4 in repeat leiomyomas.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.