Case Report: Molecularly Distinct Synchronous Uterine BRG1-Deficient and Ovarian p53- Mutant Endometrioid Carcinomas

Case Report: Molecularly Distinct Synchronous Uterine BRG1-Deficient and Ovarian p53- Mutant Endometrioid Carcinomas | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Case Report: Molecularly Distinct Synchronous Uterine BRG1-Deficient and Ovarian p53- Mutant Endometrioid Carcinomas Yuchen Sun, Jianyi Sun, Yuning Xie, Yifei Wang, Rui Ma, Zhiyong Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8294770/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Mar, 2026 Read the published version in BMC Women's Health → Version 1 posted 18 You are reading this latest preprint version Abstract Background Synchronous multiple primary malignancies (SMPMs) of the uterus and ovary are uncommon and diagnostically challenging, as they must be distinguished from metastatic spread of a single primary tumor. Accurate assessment of tumor clonality increasingly relies on integrated molecular profiling, which has important implications for staging, prognosis and therapeutic decision-making. Case Presentation We describe a 47-year-old woman presenting with abdominal distension and extensive peritoneal dissemination. Imaging revealed a uterine endometrial mass and bilateral adnexal lesions. After neoadjuvant chemotherapy, she underwent optimal cytoreductive surgery. Histopathology demonstrated a low-grade endometrioid carcinoma of the uterine corpus and a high-grade endometrioid carcinoma of the ovary. Immunohistochemistry and molecular work-up showed that the uterine tumor had wild-type p53 expression, complete loss of BRG1 and deficient mismatch repair (dMMR), whereas the ovarian tumor exhibited a p53-mutant phenotype with diffuse strong nuclear staining, retained BRG1 expression and proficient mismatch repair (pMMR). Multiple foci of endometriosis were also identified in the pelvis. Conclusions This pronounced molecular heterogeneity, particularly the distinct p53 and BRG1 profiles, provides compelling evidence for two independent primary malignancies rather than metastatic spread from a common origin. This case underscores the critical utility of comprehensive molecular profiling, emphasizing p53 and BRG1 status alongside MMR, in distinguishing genuinely independent synchronous primary gynecological tumors. Such an approach is indispensable for accurate diagnosis, prognostication, and guiding optimal personalized patient management. Synchronous multiple primary malignancies Endometrioid carcinoma BRG1 loss P53 mutation MMR status Figures Figure 1 Figure 2 Background Synchronous multiple primary malignancies (SMPMs) are defined as two or more distinct primary tumors occurring in the same individual, either simultaneously or within a short interval (usually 6 months) [ 1 – 3 ]. While relatively uncommon, their incidence has been increasing, partly due to improved diagnostic techniques and increased life expectancy [ 4 , 5 ]. In the gynecological field, synchronous endometrial and ovarian carcinomas represent the most common type of SMPMs, accounting for 5–10% of all endometrial cancers and up to 10% of endometrioid ovarian cancers [ 6 – 8 ]. These synchronous tumors often pose a diagnostic challenge in distinguishing between independent primary tumors and metastatic disease, with significant implications for prognosis and treatment planning [ 9 – 11 ]. Traditionally, histological similarities, tumor grade, and depth of myometrial invasion have been used to differentiate between these entities. However, with advances in molecular pathology, an increasing number of studies emphasize the critical role of molecular profiling in elucidating tumor clonality and biological behavior [ 12 – 14 ]. We present an intriguing case of a patient diagnosed with synchronous low-grade endometrioid carcinoma of the uterine corpus and high-grade endometrioid ovarian carcinoma. This case is remarkable for the extensive disease presentation at diagnosis, the simultaneous occurrence of histologically disparate tumors, and, most significantly, their strikingly discordant molecular profiles, most notably concerning p53 immunohistochemical (IHC) expression and the status of SWI/SNF chromatin remodeling complex components (BRG1), alongside mismatch repair (MMR) status [ 15 – 17 ]. The differential expression of these crucial molecular markers provides compelling evidence for independent primary origins, which is pivotal for accurate diagnosis and personalized treatment strategies. Additionally, the presence of concurrent endometriosis further enriches the clinical context of this rare presentation. Case Presentation A 47-year-old female presented to our hospital with a diagnosis of "endometrial carcinoma and adnexal mass." Her medical history was unremarkable. Initial workup around March 2025 revealed a uterine cavity lesion diagnosed as endometrioid adenocarcinoma based on biopsy. Concurrent imaging studies, including an abdominopelvic CT scan, demonstrated a highly suspicious solid-cystic mass in the left adnexa, measuring approximately 8.8 x 8.0 x 6.4 cm, and prominent heterogeneous enhancement within the uterine endometrium, suggestive of an endometrial lesion (Fig. 1 ). Additionally, extensive peritoneal thickening and nodularity (largest lesion 5.9 cm in the mesentery), ascites, and a suspicious right upper lobe lung nodule were noted. A subsequent gynecological ultrasound around May 2025 confirmed the left adnexal mass (BI-RADS 4–5 category) with multiple cystic areas, alongside heterogeneous endometrial echoes and pelvic free fluid. Pre-operative cardiac assessments (ECG, echocardiography, lower extremity venous ultrasound) were largely unremarkable, apart from mild valvular regurgitation, deeming her fit for surgery. Given the advanced stage, the patient initially received 4 cycles of neoadjuvant chemotherapy. Following this, around June 2025, she underwent extensive cytoreductive surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy, and partial resection of the diaphragm and pericardium due to tumor involvement. Post-operatively, she commenced adjuvant chemotherapy with paclitaxel and carboplatin, which was subsequently modified to include bevacizumab for the last two cycles (paclitaxel + carboplatin + bevacizumab). At the time of this report, the patient has completed three cycles of adjuvant therapy and is admitted for the next cycle. She reports mild, occasional brownish vaginal discharge upon activity, with no abdominal pain, nausea, vomiting, chest discomfort, palpitations, fatigue, or fever. Her appetite and sleep are good, and bowel/bladder functions are normal. Uterine Corpus: Histopathology revealed a low-grade endometrioid carcinoma. Hematoxylin and eosin (H&E) staining showed well-differentiated glandular structures with minimal nuclear atypia. Immunohistochemical staining showed positive expression for ER, PR, and P16, with a Ki67 proliferation index of 60%. P53 IHC demonstrated a wild-type pattern (scattered nuclear staining). Notably, BRG1 immunohistochemistry revealed a complete loss of nuclear expression in tumor cells, indicating a BRG1 gene deletion, while INI1 expression was retained. Crucially, the tumor exhibited an aberrant expression pattern for mismatch repair (MMR) proteins: MLH1 was positive, but MSH2 and MSH6 showed subclonal positivity (weak staining in some cells compared to internal controls), and PMS2 was positive. This pattern strongly suggested a deficient mismatch repair (dMMR) status, indicative of high microsatellite instability (MSI-H), warranting molecular testing (Fig. 2 ). Ovary: Histopathology confirmed a high-grade adenocarcinoma, favoring endometrioid type (FIGO Grade 3). H&E staining showed poorly differentiated glandular and solid growth patterns with marked nuclear pleomorphism and numerous mitotic figures. IHC staining showed ER and PR negativity, patchy P16 positivity, and a high Ki67 proliferation index of 70%. P53 IHC revealed a diffuse strong positive staining pattern, suggestive of a p53-mutant phenotype. Immunohistochemistry for BRG1 and INI1 both showed retained nuclear expression (Fig. 2 ). In contrast to the uterine tumor, all MMR proteins (MLH1, MSH2, MSH6, PMS2) were positively expressed, indicating a proficient mismatch repair (pMMR) status, corresponding to microsatellite stable (MSS). Left Fallopian Tube: Showed focal serous cell atypia, with p53 wild-type expression. Metastatic lesions: Carcinoma was identified in the diaphragm, anterior rectal wall, left sigmoid colon lesion, and omentum. These metastatic foci displayed similar histological features to the high-grade ovarian carcinoma. Endometriosis: Foci of endometriosis were identified in the bladder reflection peritoneum, left bladder surface peritoneum (PR negative in this location), and right broad ligament posterior leaf. Cervical outer os, right fallopian tube, and right ovary: All were negative for malignancy. Final Diagnosis: Left Ovarian High-Grade Endometrioid Carcinoma (FIGO Stage IIIC) status post-chemotherapy and surgery. Low-Grade Endometrioid Carcinoma of the Uterus status post-chemotherapy and surgery. Discussion This case presents a rare and complex scenario of synchronous low-grade endometrioid carcinoma of the uterine corpus and high-grade endometrioid ovarian carcinoma, characterized by extensive peritoneal dissemination at initial presentation. The most compelling aspect of this case lies in the striking molecular discordance between the two primary tumors, which holds significant clinical implications. Synchronous Multiple Primary Malignancies with Molecular Heterogeneity The coexistence of both uterine and ovarian endometrioid carcinomas often necessitates careful distinction between independent primary tumors and metastatic spread [ 18 , 19 ]. Historically, criteria such as differing histologies, low-grade uterine tumor with high-grade ovarian tumor, or presence of endometrial hyperplasia/atypia in the uterus, have suggested independent primaries [ 18 , 20 , 21 ]. Our case aligns with several of these criteria: a low-grade uterine tumor alongside a high-grade ovarian tumor. While the differing MMR statuses initially pointed towards independent origins, the most definitive evidence for distinct primary malignancies in this patient stemmed from the profound differences in p53 expression and BRG1 status. The uterine endometrioid carcinoma exhibited a dMMR/MSI-H phenotype and a complete loss of BRG1 expression, while the ovarian endometrioid carcinoma showed a pMMR/MSS phenotype with a p53-mutant signature and retained BRG1/INI1 expression. This pronounced molecular dissociation, particularly highlighting the contrasting p53 and BRG1 profiles, in conjunction with the disparate MMR statuses, strongly argues against a common clonal origin and supports two distinct primary malignancies[ 22 – 24 ]. Such molecular heterogeneity in synchronous gynecological cancers is increasingly recognized and highlights the necessity of comprehensive molecular profiling involving a broader panel of markers for each tumor, not just to distinguish independent primaries from metastases, but also to inform accurate staging, prognostication, and guide the selection of targeted therapies, particularly in the era of personalized medicine. P53 Status: Wild-Type vs. Mutant Phenotype and Clinical Significance P53, a critical tumor suppressor gene, plays a pivotal role in maintaining genomic integrity. Its expression pattern via immunohistochemistry serves as a reliable surrogate for its mutational status, which has profound prognostic and predictive value in various cancers [ 25 , 26 ]. In this case, the high-grade ovarian endometrioid carcinoma displayed a p53-mutant phenotype, characterized by diffuse strong positive staining. P53 mutations are frequently associated with high-grade, aggressive tumor behaviors, genomic instability, and resistance to certain chemotherapies [ 27 , 28 ]. In contrast, the uterine low-grade endometrioid carcinoma, along with the adjacent fallopian tube atypical serous cells, exhibited a p53 wild-type phenotype (weak or patchy staining). The presence of a wild-type p53 pattern often correlates with a less aggressive tumor biology and may confer differential responses to therapeutic interventions compared to p53-mutant tumors. This clear distinction in p53 status further reinforces the concept of two separate primary tumors, each with its own distinct molecular pathogenesis and biological trajectory. The p53 mutant phenotype in the ovarian tumor likely contributed to its aggressive presentation with widespread peritoneal carcinomatosis. SWI/SNF Complex Deficiency: BRG1 Loss in Uterine Carcinoma The detection of BRG1 loss in the uterine low-grade endometrioid carcinoma, while being retained in the ovarian tumor, provides another critical molecular distinction affirming the independent origins. The SWI/SNF chromatin remodeling complex, composed of several subunits including BRG1 (SMARCA4) and INI1 (SMARCB1), plays a vital role in gene regulation and tumor suppression [ 29 , 30 ]. Loss-of-function mutations or deletions in SWI/SNF subunits are found in a variety of human cancers, and their status can influence tumor behavior and response to therapy [ 31 , 32 ]. In endometrial carcinoma, BRG1 loss is particularly associated with lower-grade endometrioid subtypes and often co-occurs with PTEN mutations and microsatellite instability, as seen in our patient's uterine tumor [ 33 , 34 ]. The complete absence of BRG1 protein expression in the uterine tumor, in contrast to its intact expression in the ovarian tumor, further delineates their independent pathogenic pathways. This molecular difference, alongside the MMR and p53 discrepancies, adds substantial weight to the diagnosis of two distinct primary tumors, each driven by unique genetic alterations. Association with Endometriosis The concomitant finding of multiple peritoneal foci of endometriosis in this patient is also notable. Endometriosis, particularly ovarian endometriosis (endometriomas), is a well-established precursor for various types of ovarian carcinomas, most commonly endometrioid and clear cell carcinomas [ 35 – 37 ]. While direct malignant transformation was not pathologically confirmed within these peritoneal endometriotic lesions, their presence alongside the high-grade endometrioid ovarian carcinoma suggests a possible etiological link. This association could imply a chronic inflammatory microenvironment conducive to malignant transformation or shared genetic predispositions[ 38 , 39 ]. Further investigation into the molecular characteristics of these endometriotic foci versus the adjacent tumor might provide deeper insights into the precise role of endometriosis in the tumorigenesis of this patient's ovarian carcinoma. Treatment and Future Directions The patient's initial presentation with extensive peritoneal carcinomatosis and diaphragm involvement necessitated a multimodal treatment approach, including neoadjuvant chemotherapy, aggressive cytoreductive surgery, and adjuvant chemotherapy combined with bevacizumab. The current good clinical response is encouraging. However, the dMMR/MSI-H status of the uterine tumor raises the potential for immunotherapy (e.g., PD-1 inhibitors) in the event of recurrence, given the proven efficacy of immune checkpoint inhibitors in dMMR/MSI-H solid tumors [ 40 , 41 ]. In contrast, the p53-mutant and pMMR/MSS status of the ovarian tumor might suggest different therapeutic sensitivities. While the dMMR/MSI-H status of the uterine tumor and p53-mutant status of the ovarian tumor have established therapeutic implications, the BRG1 loss in the uterine tumor further contributes to its unique molecular fingerprint, which may warrant consideration in future therapeutic strategies, although direct targeted therapies for SWI/SNF deficiency are still evolving. This highlights the ongoing challenge and opportunity in tailoring future treatment strategies based on the distinct molecular profiles of each tumor. Conclusion We report a rare case of synchronous low-grade dMMR/MSI-H BRG1-deficient endometrioid carcinoma of the uterus and high-grade pMMR/MSS p53-mutant endometrioid ovarian carcinoma, presenting with extensive peritoneal disease and co-existing endometriosis. This case significantly contributes to the understanding of gynecological synchronous multiple primary malignancies by demonstrating profound molecular heterogeneity between histologically disparate tumors, specifically highlighting the utility of a multi-marker approach, with particular emphasis on p53 expression and SWI/SNF component analysis (e.g., BRG1), complemented by MMR status, in definitively distinguishing independent primary tumors. It underscores the critical need for comprehensive molecular profiling of each tumor when SMPMs are suspected, especially in cases with different histological grades, to inform accurate diagnosis, prognostication, and guide personalized therapeutic interventions. Abbreviations BRG1 Brahma-related gene 1 dMMR deficient mismatch repair FIGO International Federation of Gynecology and Obstetrics INI1 integrase interactor 1 MMR mismatch repair MSI-H microsatellite instability-high MSS microsatellite stable PD-1 programmed cell death protein 1 pMMR proficient mismatch repair PR progesterone receptor SMPMs synchronous multiple primary malignancies SWI/SNF SWItch/Sucrose Non-Fermentable chromatin-remodeling complex. Declarations Acknowledgements Not applicable Authors' contributions YS, JS and YX were major contributors in drafting the manuscript and reviewing the literature. YX, YW and RM were responsible for the clinical examinations and surgical management of the patient. ZL and LX performed the histopathological evaluation and interpreted the pathological findings. SY, MY and WS conceived and designed the study, supervised the project and critically revised the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript. Funding This project supported by the National Natural Science Foundation of China (Grant No. 82474559). Availability of data and materials The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author. Ethics approval and consent to participate Not applicable. Consent for publication Written informed consent for publication of this case report was obtained by the patient. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors’ information Yuchen Sun is a master’s student at Shandong University of Traditional Chinese Medicine, Jinan, China. References Ghosh S, Mehta AC, Abuquyyas S, Raju S, Farver C. Primary lung neoplasms presenting as multiple synchronous lung nodules. 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Cite Share Download PDF Status: Published Journal Publication published 29 Mar, 2026 Read the published version in BMC Women's Health → Version 1 posted Editorial decision: Revision requested 21 Feb, 2026 Reviews received at journal 21 Feb, 2026 Reviewers agreed at journal 12 Feb, 2026 Reviews received at journal 12 Feb, 2026 Reviews received at journal 11 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviews received at journal 29 Jan, 2026 Reviewers agreed at journal 16 Jan, 2026 Reviews received at journal 07 Jan, 2026 Reviewers agreed at journal 07 Jan, 2026 Reviewers invited by journal 07 Jan, 2026 Editor assigned by journal 19 Dec, 2025 Editor invited by journal 11 Dec, 2025 Submission checks completed at journal 11 Dec, 2025 First submitted to journal 11 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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12:53:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8294770/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8294770/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-026-04415-0","type":"published","date":"2026-03-29T16:08:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":100012040,"identity":"0de5ab14-9463-4e54-82dd-2a5415cd587c","added_by":"auto","created_at":"2026-01-12 06:12:51","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":246442,"visible":true,"origin":"","legend":"","description":"","filename":"CaseReportMolecularlyDistinctSynchronousUterineBRG1DeficientandOvarianp53MutantEndometrioidCarcinomas.docx","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/1877dbec3ff50e03957ac46b.docx"},{"id":100012039,"identity":"2690a07e-4146-4438-964f-fec801a7a745","added_by":"auto","created_at":"2026-01-12 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06:12:48","extension":"xml","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85549,"visible":true,"origin":"","legend":"","description":"","filename":"77d3135a9a9c4723845fca3cfe3b11a51structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/fdc82ea9f8eaeea48df93867.xml"},{"id":100362296,"identity":"f3140f60-c372-407d-9148-1c1d945f1b6f","added_by":"auto","created_at":"2026-01-16 07:46:32","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":95033,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/ced7a2fa42a5052d28a3de4a.html"},{"id":100011991,"identity":"b788ed3b-1399-4b0c-b0f2-f4c2e4038f5a","added_by":"auto","created_at":"2026-01-12 06:12:48","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":350067,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePre-operative abdominopelvic computed tomography (CT) scans demonstrating the primary uterine (A-E) and ovarian lesions (E-H).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/accd9f11b1c3db304b8d4c8a.jpg"},{"id":100011997,"identity":"76822e31-3029-4fa2-a73c-7adaf981c06e","added_by":"auto","created_at":"2026-01-12 06:12:48","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":529949,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eHistopathological and immunohistochemical findings of uterine and ovarian tumors.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/8e9b0055d705b17e0dff02ed.jpg"},{"id":105756191,"identity":"0e10c0ad-a2f1-4ed6-ae47-1b565dedabcb","added_by":"auto","created_at":"2026-03-30 16:37:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1317147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8294770/v1/052b2ed7-e848-41cc-8083-d4ffec3c5cde.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Case Report: Molecularly Distinct Synchronous Uterine BRG1-Deficient and Ovarian p53- Mutant Endometrioid Carcinomas","fulltext":[{"header":"Background","content":"\u003cp\u003eSynchronous multiple primary malignancies (SMPMs) are defined as two or more distinct primary tumors occurring in the same individual, either simultaneously or within a short interval (usually 6 months) [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. While relatively uncommon, their incidence has been increasing, partly due to improved diagnostic techniques and increased life expectancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In the gynecological field, synchronous endometrial and ovarian carcinomas represent the most common type of SMPMs, accounting for 5\u0026ndash;10% of all endometrial cancers and up to 10% of endometrioid ovarian cancers [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These synchronous tumors often pose a diagnostic challenge in distinguishing between independent primary tumors and metastatic disease, with significant implications for prognosis and treatment planning [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTraditionally, histological similarities, tumor grade, and depth of myometrial invasion have been used to differentiate between these entities. However, with advances in molecular pathology, an increasing number of studies emphasize the critical role of molecular profiling in elucidating tumor clonality and biological behavior [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. We present an intriguing case of a patient diagnosed with synchronous low-grade endometrioid carcinoma of the uterine corpus and high-grade endometrioid ovarian carcinoma. This case is remarkable for the extensive disease presentation at diagnosis, the simultaneous occurrence of histologically disparate tumors, and, most significantly, their strikingly discordant molecular profiles, most notably concerning p53 immunohistochemical (IHC) expression and the status of SWI/SNF chromatin remodeling complex components (BRG1), alongside mismatch repair (MMR) status [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The differential expression of these crucial molecular markers provides compelling evidence for independent primary origins, which is pivotal for accurate diagnosis and personalized treatment strategies. Additionally, the presence of concurrent endometriosis further enriches the clinical context of this rare presentation.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 47-year-old female presented to our hospital with a diagnosis of \"endometrial carcinoma and adnexal mass.\" Her medical history was unremarkable. Initial workup around March 2025 revealed a uterine cavity lesion diagnosed as endometrioid adenocarcinoma based on biopsy. Concurrent imaging studies, including an abdominopelvic CT scan, demonstrated a highly suspicious solid-cystic mass in the left adnexa, measuring approximately 8.8 x 8.0 x 6.4 cm, and prominent heterogeneous enhancement within the uterine endometrium, suggestive of an endometrial lesion (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Additionally, extensive peritoneal thickening and nodularity (largest lesion 5.9 cm in the mesentery), ascites, and a suspicious right upper lobe lung nodule were noted. A subsequent gynecological ultrasound around May 2025 confirmed the left adnexal mass (BI-RADS 4\u0026ndash;5 category) with multiple cystic areas, alongside heterogeneous endometrial echoes and pelvic free fluid. Pre-operative cardiac assessments (ECG, echocardiography, lower extremity venous ultrasound) were largely unremarkable, apart from mild valvular regurgitation, deeming her fit for surgery.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eGiven the advanced stage, the patient initially received 4 cycles of neoadjuvant chemotherapy. Following this, around June 2025, she underwent extensive cytoreductive surgery, including total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, pelvic and para-aortic lymphadenectomy, and partial resection of the diaphragm and pericardium due to tumor involvement. Post-operatively, she commenced adjuvant chemotherapy with paclitaxel and carboplatin, which was subsequently modified to include bevacizumab for the last two cycles (paclitaxel\u0026thinsp;+\u0026thinsp;carboplatin\u0026thinsp;+\u0026thinsp;bevacizumab). At the time of this report, the patient has completed three cycles of adjuvant therapy and is admitted for the next cycle. She reports mild, occasional brownish vaginal discharge upon activity, with no abdominal pain, nausea, vomiting, chest discomfort, palpitations, fatigue, or fever. Her appetite and sleep are good, and bowel/bladder functions are normal.\u003c/p\u003e \u003cp\u003eUterine Corpus: Histopathology revealed a low-grade endometrioid carcinoma. Hematoxylin and eosin (H\u0026amp;E) staining showed well-differentiated glandular structures with minimal nuclear atypia. Immunohistochemical staining showed positive expression for ER, PR, and P16, with a Ki67 proliferation index of 60%. P53 IHC demonstrated a wild-type pattern (scattered nuclear staining). Notably, BRG1 immunohistochemistry revealed a complete loss of nuclear expression in tumor cells, indicating a BRG1 gene deletion, while INI1 expression was retained. Crucially, the tumor exhibited an aberrant expression pattern for mismatch repair (MMR) proteins: MLH1 was positive, but MSH2 and MSH6 showed subclonal positivity (weak staining in some cells compared to internal controls), and PMS2 was positive. This pattern strongly suggested a deficient mismatch repair (dMMR) status, indicative of high microsatellite instability (MSI-H), warranting molecular testing (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOvary: Histopathology confirmed a high-grade adenocarcinoma, favoring endometrioid type (FIGO Grade 3). H\u0026amp;E staining showed poorly differentiated glandular and solid growth patterns with marked nuclear pleomorphism and numerous mitotic figures. IHC staining showed ER and PR negativity, patchy P16 positivity, and a high Ki67 proliferation index of 70%. P53 IHC revealed a diffuse strong positive staining pattern, suggestive of a p53-mutant phenotype. Immunohistochemistry for BRG1 and INI1 both showed retained nuclear expression (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In contrast to the uterine tumor, all MMR proteins (MLH1, MSH2, MSH6, PMS2) were positively expressed, indicating a proficient mismatch repair (pMMR) status, corresponding to microsatellite stable (MSS).\u003c/p\u003e \u003cp\u003eLeft Fallopian Tube: Showed focal serous cell atypia, with p53 wild-type expression. Metastatic lesions: Carcinoma was identified in the diaphragm, anterior rectal wall, left sigmoid colon lesion, and omentum. These metastatic foci displayed similar histological features to the high-grade ovarian carcinoma. Endometriosis: Foci of endometriosis were identified in the bladder reflection peritoneum, left bladder surface peritoneum (PR negative in this location), and right broad ligament posterior leaf. Cervical outer os, right fallopian tube, and right ovary: All were negative for malignancy.\u003c/p\u003e \u003cp\u003eFinal Diagnosis: Left Ovarian High-Grade Endometrioid Carcinoma (FIGO Stage IIIC) status post-chemotherapy and surgery. Low-Grade Endometrioid Carcinoma of the Uterus status post-chemotherapy and surgery.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case presents a rare and complex scenario of synchronous low-grade endometrioid carcinoma of the uterine corpus and high-grade endometrioid ovarian carcinoma, characterized by extensive peritoneal dissemination at initial presentation. The most compelling aspect of this case lies in the striking molecular discordance between the two primary tumors, which holds significant clinical implications.\u003c/p\u003e \u003cp\u003eSynchronous Multiple Primary Malignancies with Molecular Heterogeneity\u003c/p\u003e \u003cp\u003eThe coexistence of both uterine and ovarian endometrioid carcinomas often necessitates careful distinction between independent primary tumors and metastatic spread [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Historically, criteria such as differing histologies, low-grade uterine tumor with high-grade ovarian tumor, or presence of endometrial hyperplasia/atypia in the uterus, have suggested independent primaries [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our case aligns with several of these criteria: a low-grade uterine tumor alongside a high-grade ovarian tumor. While the differing MMR statuses initially pointed towards independent origins, the most definitive evidence for distinct primary malignancies in this patient stemmed from the profound differences in p53 expression and BRG1 status. The uterine endometrioid carcinoma exhibited a dMMR/MSI-H phenotype and a complete loss of BRG1 expression, while the ovarian endometrioid carcinoma showed a pMMR/MSS phenotype with a p53-mutant signature and retained BRG1/INI1 expression. This pronounced molecular dissociation, particularly highlighting the contrasting p53 and BRG1 profiles, in conjunction with the disparate MMR statuses, strongly argues against a common clonal origin and supports two distinct primary malignancies[\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Such molecular heterogeneity in synchronous gynecological cancers is increasingly recognized and highlights the necessity of comprehensive molecular profiling involving a broader panel of markers for each tumor, not just to distinguish independent primaries from metastases, but also to inform accurate staging, prognostication, and guide the selection of targeted therapies, particularly in the era of personalized medicine.\u003c/p\u003e \u003cp\u003eP53 Status: Wild-Type vs. Mutant Phenotype and Clinical Significance\u003c/p\u003e \u003cp\u003eP53, a critical tumor suppressor gene, plays a pivotal role in maintaining genomic integrity. Its expression pattern via immunohistochemistry serves as a reliable surrogate for its mutational status, which has profound prognostic and predictive value in various cancers [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In this case, the high-grade ovarian endometrioid carcinoma displayed a p53-mutant phenotype, characterized by diffuse strong positive staining. P53 mutations are frequently associated with high-grade, aggressive tumor behaviors, genomic instability, and resistance to certain chemotherapies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In contrast, the uterine low-grade endometrioid carcinoma, along with the adjacent fallopian tube atypical serous cells, exhibited a p53 wild-type phenotype (weak or patchy staining). The presence of a wild-type p53 pattern often correlates with a less aggressive tumor biology and may confer differential responses to therapeutic interventions compared to p53-mutant tumors. This clear distinction in p53 status further reinforces the concept of two separate primary tumors, each with its own distinct molecular pathogenesis and biological trajectory. The p53 mutant phenotype in the ovarian tumor likely contributed to its aggressive presentation with widespread peritoneal carcinomatosis.\u003c/p\u003e \u003cp\u003eSWI/SNF Complex Deficiency: BRG1 Loss in Uterine Carcinoma\u003c/p\u003e \u003cp\u003eThe detection of BRG1 loss in the uterine low-grade endometrioid carcinoma, while being retained in the ovarian tumor, provides another critical molecular distinction affirming the independent origins. The SWI/SNF chromatin remodeling complex, composed of several subunits including BRG1 (SMARCA4) and INI1 (SMARCB1), plays a vital role in gene regulation and tumor suppression [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Loss-of-function mutations or deletions in SWI/SNF subunits are found in a variety of human cancers, and their status can influence tumor behavior and response to therapy [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In endometrial carcinoma, BRG1 loss is particularly associated with lower-grade endometrioid subtypes and often co-occurs with PTEN mutations and microsatellite instability, as seen in our patient's uterine tumor [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The complete absence of BRG1 protein expression in the uterine tumor, in contrast to its intact expression in the ovarian tumor, further delineates their independent pathogenic pathways. This molecular difference, alongside the MMR and p53 discrepancies, adds substantial weight to the diagnosis of two distinct primary tumors, each driven by unique genetic alterations.\u003c/p\u003e \u003cp\u003eAssociation with Endometriosis\u003c/p\u003e \u003cp\u003eThe concomitant finding of multiple peritoneal foci of endometriosis in this patient is also notable. Endometriosis, particularly ovarian endometriosis (endometriomas), is a well-established precursor for various types of ovarian carcinomas, most commonly endometrioid and clear cell carcinomas [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. While direct malignant transformation was not pathologically confirmed within these peritoneal endometriotic lesions, their presence alongside the high-grade endometrioid ovarian carcinoma suggests a possible etiological link. This association could imply a chronic inflammatory microenvironment conducive to malignant transformation or shared genetic predispositions[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Further investigation into the molecular characteristics of these endometriotic foci versus the adjacent tumor might provide deeper insights into the precise role of endometriosis in the tumorigenesis of this patient's ovarian carcinoma.\u003c/p\u003e \u003cp\u003eTreatment and Future Directions\u003c/p\u003e \u003cp\u003eThe patient's initial presentation with extensive peritoneal carcinomatosis and diaphragm involvement necessitated a multimodal treatment approach, including neoadjuvant chemotherapy, aggressive cytoreductive surgery, and adjuvant chemotherapy combined with bevacizumab. The current good clinical response is encouraging. However, the dMMR/MSI-H status of the uterine tumor raises the potential for immunotherapy (e.g., PD-1 inhibitors) in the event of recurrence, given the proven efficacy of immune checkpoint inhibitors in dMMR/MSI-H solid tumors [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. In contrast, the p53-mutant and pMMR/MSS status of the ovarian tumor might suggest different therapeutic sensitivities. While the dMMR/MSI-H status of the uterine tumor and p53-mutant status of the ovarian tumor have established therapeutic implications, the BRG1 loss in the uterine tumor further contributes to its unique molecular fingerprint, which may warrant consideration in future therapeutic strategies, although direct targeted therapies for SWI/SNF deficiency are still evolving. This highlights the ongoing challenge and opportunity in tailoring future treatment strategies based on the distinct molecular profiles of each tumor.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWe report a rare case of synchronous low-grade dMMR/MSI-H BRG1-deficient endometrioid carcinoma of the uterus and high-grade pMMR/MSS p53-mutant endometrioid ovarian carcinoma, presenting with extensive peritoneal disease and co-existing endometriosis. This case significantly contributes to the understanding of gynecological synchronous multiple primary malignancies by demonstrating profound molecular heterogeneity between histologically disparate tumors, specifically highlighting the utility of a multi-marker approach, with particular emphasis on p53 expression and SWI/SNF component analysis (e.g., BRG1), complemented by MMR status, in definitively distinguishing independent primary tumors. It underscores the critical need for comprehensive molecular profiling of each tumor when SMPMs are suspected, especially in cases with different histological grades, to inform accurate diagnosis, prognostication, and guide personalized therapeutic interventions.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBRG1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBrahma-related gene 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003edMMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edeficient mismatch repair\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Federation of Gynecology and Obstetrics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eINI1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eintegrase interactor 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emismatch repair\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMSI-H\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emicrosatellite instability-high\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emicrosatellite stable\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD-1\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogrammed cell death protein 1\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003epMMR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eproficient mismatch repair\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogesterone receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSMPMs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003esynchronous multiple primary malignancies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSWI/SNF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSWItch/Sucrose Non-Fermentable chromatin-remodeling complex.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYS, JS and YX were major contributors in drafting the manuscript and reviewing the literature. YX, YW and RM were responsible for the clinical examinations and surgical management of the patient. ZL and LX performed the histopathological evaluation and interpreted the pathological findings. SY, MY and WS conceived and designed the study, supervised the project and critically revised the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis project supported by the National Natural Science Foundation of China (Grant No. 82474559).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of this case report was obtained by\u003c/p\u003e\n\u003cp\u003ethe patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuchen Sun is a master’s student at Shandong University of Traditional Chinese Medicine, Jinan, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eGhosh S, Mehta AC, Abuquyyas S, Raju S, Farver C. 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Virchows Arch. 2021;478(1):21\u0026ndash;30.\u003c/li\u003e\n \u003cli\u003eMurali R, Davidson B, Fadare O, Carlson JA, Crum CP, Gilks CB, et al. High-grade endometrial carcinomas: morphologic and immunohistochemical features, diagnostic challenges and recommendations. Int J Gynecol Pathol. 2019;38(Suppl 1):S40\u0026ndash;S63.\u003c/li\u003e\n \u003cli\u003eImyanitov EN, Hanson KP. Molecular pathogenesis of bilateral breast cancer. Cancer Lett. 2003;191(1):1\u0026ndash;7.\u003c/li\u003e\n \u003cli\u003eGadducci A, Multinu F, De Vitis LA, Cosio S, Carinelli S, Aletti GD. Endometrial stromal tumors of the uterus: epidemiology, pathological and biological features, treatment options and clinical outcomes. Gynecol Oncol. 2023;171:95\u0026ndash;105.\u003c/li\u003e\n \u003cli\u003eEspinosa I, D\u0026rsquo;Angelo E, Prat J. Endometrial carcinoma: 10 years of TCGA (The Cancer Genome Atlas): a critical reappraisal with comments on FIGO 2023 staging. Gynecol Oncol. 2024;186:94\u0026ndash;103.\u003c/li\u003e\n \u003cli\u003eWang F, Chen G, Zhang Z, Yuan Y, Wang Y, Gao YH, Sheng W, Wang Z, Li X, Yuan X, et al. The Chinese Society of Clinical Oncology (CSCO) clinical guidelines for the diagnosis and treatment of colorectal cancer: 2024 update. Cancer Commun (Lond). 2025;45(3):332\u0026ndash;379.\u003c/li\u003e\n \u003cli\u003eFu X, Huang J, Zhu J, Fan X, Wang C, Deng W, Tan X, Chen Z, Cai Y, Lin H, et al. Prognosis and immunotherapy efficacy in dMMR and MSS colorectal cancer patients and an MSI status predicting model. Int J Cancer. 2024;155(4):766\u0026ndash;775.\u003c/li\u003e\n \u003cli\u003eHuang J, Xu L, Cai Y, Tan X, Lin H, Chen Z, Wang C, Deng W, Fu X. Certain pMMR colorectal cancer patients should undergo additional MSI-PCR testing to reduce the risk of misdiagnosing MSI-H and Lynch syndrome. BMC Cancer. 2025;25(1):1103.\u003c/li\u003e\n \u003cli\u003eRaffone A, Travaglino A, Cerbone M, De Luca C, Russo D, Di Maio A, et al. Diagnostic accuracy of p53 immunohistochemistry as surrogate of TP53 sequencing in endometrial cancer. Pathol Res Pract. 2020;216(8):153025.\u003c/li\u003e\n \u003cli\u003eK\u0026ouml;bel M, Ronnett BM, Singh N, Soslow RA, Gilks CB, McCluggage WG. Interpretation of p53 immunohistochemistry in endometrial carcinomas: toward increased reproducibility. Int J Gynecol Pathol. 2019;38(Suppl 1):S123\u0026ndash;31.\u003c/li\u003e\n \u003cli\u003eNegrini S, Gorgoulis VG, Halazonetis TD. Genomic instability\u0026mdash;an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010;11(3):220\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eZhang C, Liu J, Xu D, Zhang T, Hu W, Feng Z. Gain-of-function mutant p53 in cancer progression and therapy. J Mol Cell Biol. 2020;12(9):674\u0026ndash;87.\u003c/li\u003e\n \u003cli\u003eAndrades A, Peinado P, Alvarez-Perez JC, Sanjuan-Hidalgo JM, Garc\u0026iacute;a DJ, Arenas AM, et al. SWI/SNF complexes in hematological malignancies: biological implications and therapeutic opportunities. Mol Cancer. 2023;22(1):39.\u003c/li\u003e\n \u003cli\u003eCenik BK, Shilatifard A. COMPASS and SWI/SNF complexes in development and disease. Nat Rev Genet. 2021;22(1):38\u0026ndash;58.\u003c/li\u003e\n \u003cli\u003eGr\u0026uuml;newald TGP, Postel-Vinay S, Nakayama RT, Berlow NE, Bolzicco A, Cerullo V, et al. Translational aspects of epithelioid sarcoma: current consensus. Clin Cancer Res. 2024;30(6):1079\u0026ndash;92.\u003c/li\u003e\n \u003cli\u003eMardinian K, Adashek JJ, Botta GP, Kato S, Kurzrock R. SMARCA4: implications of an altered chromatin-remodeling gene for cancer development and therapy. Mol Cancer Ther. 2021;20(12):2341\u0026ndash;51.\u003c/li\u003e\n \u003cli\u003eNavickas SM, Giles KA, Brettingham-Moore KH, Taberlay PC. The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target. Oncogene. 2023;42(31):2363\u0026ndash;73.\u003c/li\u003e\n \u003cli\u003eNambiarajan A, Singh V, Bhardwaj N, Mittal S, Kumar S, Jain D. SMARCA4/BRG1-deficient non-small-cell lung carcinomas: a case series and review of the literature. Arch Pathol Lab Med. 2021;145(1):90\u0026ndash;8.\u003c/li\u003e\n \u003cli\u003eGuidozzi F. Endometriosis-associated cancer. Climacteric. 2021;24(6):587\u0026ndash;92.\u003c/li\u003e\n \u003cli\u003eSteinbuch SC, L\u0026uuml;\u0026szlig; AM, Eltrop S, G\u0026ouml;tte M, Kiesel L. Endometriosis-associated ovarian cancer: from molecular pathologies to clinical relevance. Int J Mol Sci. 2024;25(8):4306.\u003c/li\u003e\n \u003cli\u003eKajiyama H, Suzuki S, Yoshihara M, Tamauchi S, Yoshikawa N, Niimi K, et al. Endometriosis and cancer. Free Radic Biol Med. 2019;133:186\u0026ndash;192.\u003c/li\u003e\n \u003cli\u003eSymons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, Tayade C. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24(9):748\u0026ndash;762.\u003c/li\u003e\n \u003cli\u003eOrisaka M, Mizutani T, Miyazaki Y, Shirafuji A, Tamamura C, Fujita M, Tsuyoshi H, Yoshida Y. Chronic low-grade inflammation and ovarian dysfunction in women with polycystic ovarian syndrome, endometriosis, and aging. Front Endocrinol (Lausanne). 2023;14:1324429.\u003c/li\u003e\n \u003cli\u003eBhamidipati D, Subbiah V. Tumor-agnostic drug development in dMMR/MSI-H solid tumors. Trends Cancer. 2023;9(10):828\u0026ndash;839.\u003c/li\u003e\n \u003cli\u003eAwosika JA, Gulley JL, Pastor DM. Deficient mismatch repair and microsatellite instability in solid tumors. Int J Mol Sci. 2025;26(9):4394.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Synchronous multiple primary malignancies, Endometrioid carcinoma, BRG1 loss, P53 mutation, MMR status","lastPublishedDoi":"10.21203/rs.3.rs-8294770/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8294770/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSynchronous multiple primary malignancies (SMPMs) of the uterus and ovary are uncommon and diagnostically challenging, as they must be distinguished from metastatic spread of a single primary tumor. Accurate assessment of tumor clonality increasingly relies on integrated molecular profiling, which has important implications for staging, prognosis and therapeutic decision-making.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe describe a 47-year-old woman presenting with abdominal distension and extensive peritoneal dissemination. Imaging revealed a uterine endometrial mass and bilateral adnexal lesions. After neoadjuvant chemotherapy, she underwent optimal cytoreductive surgery. Histopathology demonstrated a low-grade endometrioid carcinoma of the uterine corpus and a high-grade endometrioid carcinoma of the ovary. Immunohistochemistry and molecular work-up showed that the uterine tumor had wild-type p53 expression, complete loss of BRG1 and deficient mismatch repair (dMMR), whereas the ovarian tumor exhibited a p53-mutant phenotype with diffuse strong nuclear staining, retained BRG1 expression and proficient mismatch repair (pMMR). Multiple foci of endometriosis were also identified in the pelvis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis pronounced molecular heterogeneity, particularly the distinct p53 and BRG1 profiles, provides compelling evidence for two independent primary malignancies rather than metastatic spread from a common origin. This case underscores the critical utility of comprehensive molecular profiling, emphasizing p53 and BRG1 status alongside MMR, in distinguishing genuinely independent synchronous primary gynecological tumors. Such an approach is indispensable for accurate diagnosis, prognostication, and guiding optimal personalized patient management.\u003c/p\u003e","manuscriptTitle":"Case Report: Molecularly Distinct Synchronous Uterine BRG1-Deficient and Ovarian p53- Mutant Endometrioid Carcinomas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-12 06:12:39","doi":"10.21203/rs.3.rs-8294770/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-21T11:54:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-21T08:46:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"191287400630106280989242466037031584684","date":"2026-02-12T22:02:57+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-12T11:07:25+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-11T22:08:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"154444357476741962083180804238782566822","date":"2026-02-11T07:03:13+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196661723691880246083204396717993537006","date":"2026-02-11T06:16:32+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"275888794066955337997499503424310107562","date":"2026-02-11T04:10:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"210289868461230322180977174651548370385","date":"2026-02-11T00:05:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-29T15:06:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"332796072987815892720104410730036103207","date":"2026-01-16T11:00:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-08T02:16:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"134754875024285652599079521121504152902","date":"2026-01-08T01:20:51+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T10:48:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-19T13:16:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-11T17:19:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-11T13:58:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2025-12-11T13:47:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5aa3a649-84d1-4bed-bf2c-2578cea9c36e","owner":[],"postedDate":"January 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-03-30T16:37:18+00:00","versionOfRecord":{"articleIdentity":"rs-8294770","link":"https://doi.org/10.1186/s12905-026-04415-0","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2026-03-29 16:08:45","publishedOnDateReadable":"March 29th, 2026"},"versionCreatedAt":"2026-01-12 06:12:39","video":"","vorDoi":"10.1186/s12905-026-04415-0","vorDoiUrl":"https://doi.org/10.1186/s12905-026-04415-0","workflowStages":[]},"version":"v1","identity":"rs-8294770","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8294770","identity":"rs-8294770","version":["v1"]},"buildId":"WvIrzKhiLBfengagbw6Ux","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}