STUDY QUESTION Is there an association between the somatic loss of PTEN (phosphatase and tensin homolog) and ARID1A (AT-rich interaction domain 1A) and endometriosis disease severity and worse clinical outcomes? SUMMARY ANSWER Somatic PTEN loss in endometriosis epithelium was associated with greater disease burden and subsequent surgical complexity. WHAT IS KNOWN ALREADY Somatic cancer-driver mutations including those involving the PTEN and ARID1A genes exist in endometriosis without cancer; however, their clinical impact remains unclear. STUDY DESIGN, SIZE, DURATION This prospective longitudinal study involved endometriosis tissue and clinical data from 126 participants who underwent surgery at a tertiary center for endometriosis (2013–2017), with a follow-up period of 5–9 years. PARTICIPANTS/MATERIALS, SETTING, METHODS PTEN and ARID1A loss was assessed using established immunohistochemistry (IHC) methods as proxies for somatic loss by two independent raters. PTEN and ARID1A status for each participant was defined as loss (loss in at least one sample for a participant) or retained (no loss in all samples for a participant). Primary analyses examined associations between PTEN and ARID1A loss and disease burden based on anatomic subtype (superficial peritoneal endometriosis (SUP), deep endometriosis (DE), ovarian endometrioma (OMA)) and rASRM stage (I–IV). Secondary analyses explored associations of PTEN and ARID1A loss with demographics, surgical difficulty, and pain scores (baseline and follow-up). Additionally, using previously published data on KRAS codon 12 mutations for this cohort, we investigated associations between variables in the primary and secondary analyses and acquiring two or more somatic events (PTEN loss, ARID1A loss, or KRAS mutation) in this cohort. The risk of reoperation over the 5–9 years was also examined. MAIN RESULTS AND THE ROLE OF CHANCE PTEN loss (68.3%; 86 participants) exceeded ARID1A loss (24.6%; 31 participants). Inter-rater reliability was substantial for PTEN (k = 0.69; 95% CI: 0.62–0.77) and ARID1A (k = 0.64; 95% CI: 0.51–0.77). PTEN loss was significantly associated with more severe anatomic subtypes (P < 0.001; participants with SUP only = 46.4%; participants with DE only or OMA only = 72.7%; participants with mixed subtypes = 85.1%), and higher stages (P = 0.024; Stage I = 47.8%; Stage II = 73.7%; Stage III = 80.8%; Stage IV = 81.0%). Results were similar for ARID1A loss, albeit with smaller sample size limiting power. PTEN loss was further associated with non-White ethnicities (P = 0.017) and greater surgical difficulty (more frequent need for ureterolysis) (P = 0.02). There were no differences in pain scores (baseline or follow-up) based on PTEN or ARID1A status. Reoperation was uncommon (13.5% of the cohort), and patterns in reoperation rates based on the presence of somatic alterations did not reach statistical significance. LIMITATIONS, REASONS FOR CAUTION Sequencing was not performed to determine the type of PTEN and ARID1A somatic mutations resulting in loss of expression. WIDER IMPLICATIONS OF THE FINDINGS These results demonstrate a link between PTEN somatic loss and greater endometriosis disease burden. These findings underscore the potential relevance of PTEN loss and other somatic driver mutations in a future molecular classification of endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by Canadian Institutes of Health Research (CIHR) project grant (MOP-142273 and PJT-156084). P.J.Y. was supported by a Health Professional Investigator award from Michael Smith Health Research BC, Canada, and a Canada Research Chair (Tier 2) in Endometriosis and Pelvic Pain. M.S.A. was supported by a Michael Smith Health Research BC Scholar award, and CIHR project grants (369990, 462997, and 456767). The sponsors did not play any role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. C.A. declares receiving payment from Pfizer for a symposium; being on advisory boards for AbbVie and Pfizer; being President and past President of the Canadian Society for the Advancement of Gynecologic Excellence (CanSAGE), co-lead of EndoAct Canada, and a board member of IPPS. M.A.B. has received consulting fees from AbbVie and Pfizer and grants from Ferring outside the scope of this work. D.G.H. is the founder of Canxeia Health but has no current affiliation. M.K. has received consulting fees from Helix Biopharma outside the scope of this work. M.S.A. received reimbursement of travel and registration fees to attend and present at the 2023 and 2024 annual meetings for the Society for Reproductive Investigation (SRI). P.J.Y. declares receiving: payment for a lecture from the International Society for the Study of Women’s Sexual Health (ISSWSH); honoraria from the CIHR; support to attend meetings from CanSAGE, ISSWSH, the International Pelvic Pain Society, the World Endometriosis Society (WES), the Society for the Study of Reproduction, and the Vulvodynia Summit; and discounted devices from Ohnut Wearable for a clinical trial. P.J.Y. is a data safety monitoring board member of a clinical trial funded by CIHR; and a strategic advisory board member for the Women’s Health Research Institute. P.J.Y. served as a board of directors member for CanSAGE and ISSWSH; was a junior board of directors member for WES; is a current board of directors member for WES; and was a committee chair for the Society of Obstetricians and Gynaecologists of Canada. A subset of these results was presented by the first author at the 71st Society for Reproductive Investigation Annual Scientific Meeting on 15 March 2024. Other authors have nothing to declare. TRIAL REGISTRATION NUMBER N/A.

中文翻译：

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体细胞 PTEN 和 ARID1A 丢失和子宫内膜异位症疾病负担：一项纵向研究


研究问题PTEN（磷酸酶和张力蛋白同源物）和 ARID1A（富含 AT 的相互作用域 1A）的体细胞丢失与子宫内膜异位症疾病严重程度和更差的临床结果之间是否存在关联？摘要 答案 子宫内膜异位症上皮细胞体细胞 PTEN 丢失与更大的疾病负担和随后的手术复杂性相关。已知的体细胞癌驱动突变，包括涉及 PTEN 和 ARID1A 基因的突变，存在于无癌症的子宫内膜异位症中;然而，它们的临床影响仍不清楚。研究设计、大小、持续时间 这项前瞻性纵向研究涉及 126 名参与者的子宫内膜异位症组织和临床数据，这些参与者在三级子宫内膜异位症中心（2013-2017 年）接受了手术，随访期为 5-9 年。参与者/材料、设置、方法PTEN 和 ARID1A 损失使用已建立的免疫组织化学 （IHC） 方法作为两个独立评分者的体细胞损失的代理进行评估。每个参与者的 PTEN 和 ARID1A 状态被定义为损失（参与者至少一个样本的损失）或保留（参与者的所有样本均无损失）。初步分析根据解剖亚型 （浅表腹膜子宫内膜异位症 （SUP）、深部子宫内膜异位症 （DE）、卵巢子宫内膜异位症 （OMA）） 和 rASRM 分期 （I-IV） 检查 PTEN 和 ARID1A 丢失与疾病负担之间的关联。二次分析探讨了 PTEN 和 ARID1A 丢失与人口统计学、手术难度和疼痛评分 （基线和随访） 的关联。此外，使用先前发表的有关该队列的 KRAS 密码子 12 突变的数据，我们研究了主要和次要分析中变量之间的关联，并在该队列中获得两个或多个体细胞事件 （PTEN 缺失、ARID1A 缺失或 KRAS 突变）。 还检查了 5-9 年内再次手术的风险。主要结果和机会 PTEN 损失 （68.3%;86 名参与者） 超过了 ARID1A 损失 （24.6%;31 名参与者）。PTEN （k = 0.69;95% CI： 0.62-0.77） 和 ARID1A （k = 0.64;95% CI： 0.51-0.77） 的评分者间信度很高。PTEN 丢失与更严重的解剖亚型 （P < 0.001;仅 SUP 的参与者 = 46.4%;仅 DE 或仅 OMA 的参与者 = 72.7%;混合亚型 = 85.1%） 和更高的分期 （P = 0.024;I 期 = 47.8%;II 期 = 73.7%;III 期 = 80.8%;IV 期 = 81.0%）。ARID1A 损失的结果相似，尽管样本量限制能力较小。PTEN 丢失与非白人种族 （P = 0.017） 和更大的手术难度 （更频繁地需要输尿管溶解术） （P = 0.02） 进一步相关。基于 PTEN 或 ARID1A 状态的疼痛评分 （基线或随访） 没有差异。再次手术不常见 （占队列的 13.5%），基于躯体改变存在的再手术率模式未达到统计学意义。局限性，谨慎的原因 未进行测序以确定导致表达丢失的 PTEN 和 ARID1A 体细胞突变的类型。研究结果的更广泛意义这些结果表明 PTEN 体细胞丢失与子宫内膜异位症疾病负担增加之间存在联系。这些发现强调了 PTEN 丢失和其他体细胞驱动突变在未来子宫内膜异位症分子分类中的潜在相关性。研究资金/竞争利益 本研究由加拿大卫生研究院 （CIHR） 项目资助 （MOP-142273 和 PJT-156084）。PJ 年 得到了加拿大不列颠哥伦比亚省迈克尔史密斯健康研究中心的健康专业研究员奖以及子宫内膜异位症和盆腔疼痛的加拿大研究主席（第 2 层）的支持。MSA 得到了 Michael Smith Health Research BC Scholar 奖和 CIHR 项目资助（369990、462997 和 456767）的支持。申办方在研究设计中没有发挥任何作用;在数据的收集、分析和解释方面;在撰写报告时;以及提交文章发表的决定。C.A. 声明收到辉瑞公司支付的研讨会费用;担任 AbbVie 和 Pfizer 的顾问委员会成员;曾担任加拿大妇科卓越促进协会 （CanSAGE） 的主席和前任主席、EndoAct Canada 的联合负责人以及 IPPS 的董事会成员。M.A.B. 在这项工作范围之外收到了 AbbVie 和 Pfizer 的咨询费以及 Ferring 的资助。DGH 是 Canxeia Health 的创始人，但目前没有隶属关系。M.K. 在这项工作范围之外从 Helix Biopharma 收到了咨询费。MSA 收到了参加生殖研究学会 （SRI） 2023 年和 2024 年年会的差旅费和注册费报销。P.J.Y. 宣布收到：国际妇女性健康研究学会 （ISSWSH） 的讲座费;CIHR 的酬金;支持参加来自 CanSAGE、ISSWSH、国际盆腔疼痛协会、世界子宫内膜异位症协会 （WES）、生殖研究协会和外阴痛峰会的会议;以及 Ohnut Wearable 的折扣设备用于临床试验。PJ 年 是 CIHR 资助的临床试验的数据安全监测委员会成员;以及妇女健康研究所的战略顾问委员会成员。PJ 曾担任 CanSAGE 和 ISSWSH 的董事会成员;曾是 WES 的初级董事会成员;是 WES 的现任董事会成员;并且是加拿大妇产科医师协会的委员会主席。这些结果的一个子集由第一作者在 2024 年 3 月 15 日的第 71 届生殖研究学会年度科学会议上提出。其他作者没有什么可声明的。试验注册号 N/A。