Somatic PTEN and ARID1A loss and endometriosis disease burden: a longitudinal study

Abstract

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.

Keywords: KRAS; ARID1A; PTEN; endometriosis; mutation; somatic events.

Figure 1.

Study flow chart. Included and excluded participants throughout the study.

Figure 2.

Somatic phenotype of the cohort. Description and distribution of the study’s somatic phenotype based on participants with data for PTEN, ARID1A, and KRAS (n = 113). The most frequent somatic phenotype per participant assessment was PTEN loss and KRAS mutation (with ARID1A retained) (28.3%; 32/113), followed by PTEN loss only (21.2%; 24/113), and the detection of all three somatic events (PTEN + KRAS + ARID1A) (15.9%; 18/113). Additionally, 16.8% of this cohort had none of the somatic events, and 0.9% of participants had ARID1A as the only event detected.

Figure 3.

Distribution of somatic phenotypes stratified by anatomic subtype and stage. (A) Anatomic subtype: There is a substantial difference in the proportion of participants with co-events in PTEN, ARID1A, and KRAS among the ovarian endometrioma (OMA) or deep endometriosis (DE) only, and mixed anatomic subtypes, compared to those with superficial peritoneal endometriosis (SUP) only. Additionally, having no event or only one event (PTEN, ARID1A, or KRAS mutation) was most common among participants with SUP only. (B) Stage: Co-occurrence of the three events in a participant was observed exclusively in advanced stages (Stage II–IV). Stage I had the largest proportion of individuals with no events or those with only one event.

Figure 4.

Kaplan–Meier survival analysis for reoperation risk for the follow-up period of 5–9 years. Kaplan–Meier curve depicting reoperation-free survival based on somatic phenotype for individuals with complete data available for PTEN, ARID1A, and KRAS mutation (n = 113); reoperation occurred in (11.3%; 15/113) of these cases. There was no significant association between reoperation at follow-up and somatic phenotype in the cohort (P = 0.44). However, participants with PTEN loss and KRAS mutation (without ARID1A loss) showed the lowest reoperation-free survival.

Figure 5.

Kaplan–Meier survival analysis of a sub-analysis excluding participants with a prior hysterectomy before the index surgery or who underwent a hysterectomy at our site during the index surgery. The graph includes data for individuals within this sub-group with complete data available on PTEN, ARID1A, and KRAS mutation (n = 79); reoperation occurred in 16.5% (13/79) of these cases. The sub-analysis also showed no significant association between reoperation at follow-up and somatic phenotype in the cohort (P = 0.77), but participants with PTEN loss and KRAS mutation (without ARID1A loss) showed the lowest reoperation-free survival.