Yan Liu

Decoding UTROSCT heterogeneity: systematic clinicopathological evaluation combined with molecular profiling

Abstract Uterine tumor resembling ovarian sex cord tumor (UTROSCT) constitutes an exceptionally rare histological subset of uterine mesenchymal neoplasms. While most cases have benign clinical behavior, a subset of UTROSCTs exhibits clinically aggressive behavior characterized by recurrence and metastasis. Here, we present a cohort of 25 UTROSCT cases molecularly confirmed by recurrent fusion gene detection, including ESR1::NCOA3 ( n  = 12), GREB1::NCOA1 ( n  = 6), ESR1::NCOA2 ( n  = 3), GREB1::NCOA2 ( n  = 2), GREB1::SS18 ( n  = 1), and GREB1::CTNNB1 ( n  = 1). Notably, six cases (6/25, 24%) demonstrated recurrence/metastasis: two cases showed intrauterine recurrence (harboring ESR1::NCOA3 and GREB1::NCOA1 fusions), while four developed extrauterine metastases (carrying ESR1::NCOA3 , ESR1::NCOA2, GREB1::NCOA1, and GREB1::NCOA2 fusions), with one fatality. To dissect the biological basis of UTROSCT aggressiveness, we performed integrated clinicopathologic, immunohistochemical, and molecular profiling. Multivariate analysis identified tumor size >5 cm, FIGO stage IB, and lymphovascular space invasion (LVSI) as independent predictors of recurrence/metastasis, whereas histologic features, proliferation index, and fusion gene subtypes lacked prognostic significance. Multi‐omics analysis of primary versus metastatic tumors revealed striking copy number variations (CNVs) exclusively in metastatic lesions. Specifically, heterozygous losses of SMARCB1 (2/4 metastatic cases) and ATRX (1/4 metastatic cases) were identified; both play critical roles in chromatin remodeling. These genetic alterations were conspicuously absent in primary tumors, suggesting their potential role in metastatic progression. Our findings represent the first demonstration of CNV‐driven oncogenic evolution in UTROSCTs, particularly implicating SWI/SNF complex dysregulation in metastatic competence.

UBE2C -mediated Autophagy Inhibition via Ubiquitination of SIRT1 Contributes to Endometrial Cancer Progression

Abstract Recent studies have shown that autophagy plays an important role in gynecologic tumors, and ubiquitin modification of autophagy regulatory components is essential to regulate autophagic flux. In this study, we found that the ubiquitin-conjugating enzyme E2C (UBE2C) affects endometrial cancer cell apoptosis and proliferation by inhibiting autophagy. Electron microscopy observation of cell ultrastructure and experimental biochemical analysis showed that endometrial cancer cells with UBE2C expression knocked down display typical autophagic characteristics. Cells were cotreated with the autophagy pharmacologic inhibitors chloroquine and/or bafilomycin A1, and mRFP-GFP-LC3 assays were performed to monitor autophagic flux and determine whether UBE2C suppresses the autophagy program. Investigation of the corresponding mechanism by which UBE2C inhibits autophagy revealed that UBE2C induces K48-linked SIRT1 ubiquitination and promotes ubiquitination-dependent degradation of SIRT1, subsequently reducing H4K16 deacetylation levels and epigenetically inhibiting the expression of autophagy-related genes. The results of cell counting kit-8, Hoechst staining, and immunofluorescence assays further indicated that deletion of the autophagy-related gene BECN1 significantly attenuates UBE2C knockdown–induced cell apoptosis. Moreover, overexpression of UBE2C promoted tumor growth in the xenograft mice model. While, the introduction of rapamycin, an agonist of autophagy, successfully reversed tumor growth and apoptosis inhibition mediated by UBE2C overexpression in vitro and in vivo. Taken together, our results suggested that UBE2C-mediated ubiquitination and degradation of SIRT1 contribute to the malignant progression of endometrial cancer through epigenetic inhibition of autophagy. Implications: Our study highlights the tumorigenic role and regulatory mechanism of UBE2C in endometrial cancer; UBE2C inhibits endometrial cancer cell apoptosis through autophagy-related mechanisms and our findings provide new insights into the treatment of endometrial cancer.

Integrated morphological, immunohistochemical, and genomic profiling identifies uterine leiomyoma patients with hereditary leiomyomatosis and renal cell cancer syndrome: a comprehensive analysis of 252 cases

Abstract Fumarate hydratase‐deficient uterine leiomyomas (FHd‐ULMs) represent a molecularly distinct subgroup of smooth muscle tumours associated with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. This study determined the detection rate of germline pathogenic FH variants in FHd‐ULMs using paired tumour‐normal sequencing and assessed the utility of integrated morphological, immunohistochemical (FH/2SC), genomic, and clinical features for selecting cases suspected of HLRCC. Histopathological assessment of the 252 FHd‐ULMs revealed consistent morphological features, whereas molecular profiling identified three biologically distinct categories. Germline FH ‐mutated (hereditary) cases constituted 35.7% (74/207) of this FHd‐ULM cohort, four of which showed concomitant somatic copy‐number alterations. This contrasted with the somatic‐mutated subgroup, which comprised 50.7% (105/207), including 18.4% (38/207) with isolated somatic copy‐number losses. The remaining 13.6% (28/207), though lacking detectable FH mutations, were classified with somatic‐mutated cases as sporadic FHd‐ULMs based on shared clinicopathological features. Molecular analysis identified shared variant distributions across exons 2–10, with exons 5 and 7 in the fumarate lyase domain emerging as the predominant mutational hotspots. Notably, truncating mutations showed significantly higher prevalence in hereditary cases versus somatic variants ( p  < 0.01). Clinically, hereditary FHd‐ULMs presented at younger ages (< 45 years) and manifested more aggressive phenotypes, including elevated rates of infertility (54.1% versus 26.4%), multifocal tumour development (86.5% versus 53.4%), increased surgical interventions (44.6% versus 11.5%), and familial leiomyoma clustering (51.4% versus 24.2%). Our results identify germline FH mutations, which confer significant HLRCC risk, in 35.7% of FHd‐ULMs, while somatic alterations account for the majority of cases. To ensure efficient resource allocation, we propose a stratified diagnostic approach: initial universal FH/2SC immunohistochemical screening for ULMs displaying ≥ 3 FH‐deficient morphological features, followed by confirmatory genetic testing in high‐risk individuals, defined by either aberrant FH/2SC immunoreactivity or, in immunohistochemically normal cases, age < 45 years together with a personal/family history of multiple symptomatic leiomyomas or HLRCC‐associated neoplasms. © 2026 The Pathological Society of Great Britain and Ireland.

Efficacy of a WeChat-Based, Multidisciplinary, Full-Course Nutritional Management Program on the Nutritional Status of Patients With Ovarian Cancer Undergoing Chemotherapy: Randomized Controlled Trial

Abstract Background As the most malignant type of cancer in the female reproductive system, ovarian cancer (OC) has become the second leading cause of death among Chinese women. Chemotherapy is the main treatment for patients with OC, and its numerous adverse effects can easily lead to malnutrition. It is difficult to centrally manage patients with OC in the intervals between chemotherapy. The use of WeChat, an effective mobile tool, in chronic disease management has been highlighted. Objective This study aimed to implement a continuous follow-up strategy and health monitoring based on the WeChat platform for patients with OC undergoing chemotherapy to ensure that each phase of chemotherapy was delivered on schedule and to improve the survival rate of patients with OC. Methods Participants were recruited and randomly assigned to either the WeChat-based nutrition intervention group or the usual care group. A self-administered general information questionnaire was used at enrollment to obtain basic information about the patients. The Patient-Generated Subjective Global Assessment (PG-SGA) Scale was used to investigate the nutritional status of the patients at 3 time points (T0=before the first admission to the hospital for chemotherapy, T1=2 weeks after the first chemotherapy, and T6=2 weeks after the sixth chemotherapy). The blood indices of patients were investigated through the inhospital health care system at 3 times（T0=before the first admission to the hospital for chemotherapy, T1=2 weeks after the first chemotherapy, and T6=2 weeks after the sixth chemotherapy). Patients in the intervention group were introduced to the nutrition applet, invited to join the nutrition management group chat, and allowed to consult on nutritional issues in private chats with nutrition management team members. Linear mixed models were used to analyze changes in each nutritional indicator in the 2 groups, with their baseline measurements as covariates; with group, time, and group-time interactions considered as fixed effects; and with patients considered as random effects. Results A total of 96 patients with OC undergoing chemotherapy were recruited into the study. Distribution was based on a 1:1 ratio, with 48 patients each in the nutrition intervention group and the usual care group. The attrition rate after the first chemotherapy session was 18.75%. The mixed linear model revealed that the group-based effect and the group-time interaction effect on PG-SGA scores were significant (F38,38=4.763, P=.03; F37,37=6.368, P=.01), whereas the time-based effect on PG-SGA scores was not (F38,38=0.377; P=.54). The findings indicated that the group-based effect, the time-based effect, and the group-time interaction effect on nutrition-inflammation composite indices were significant (F38,38=7.653, P=.006; F38,38=13.309, P<.001; F37,37=92.304, P<.001; F37,38=110.675, P<.001; F38,38=10.379, P=.002; and F37,37=5.289, P=.02). Conclusions This study provided evidence that a WeChat-based, multidisciplinary, full-course nutritional management program can significantly improve the nutritional status of patients with OC during chemotherapy.

Targeting polyploid giant cancer cells potentiates a therapeutic response and overcomes resistance to PARP inhibitors in ovarian cancer

To understand the mechanism of acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib, we induced the formation of polyploid giant cancer cells (PGCCs) in ovarian and breast cancer cell lines, high-grade serous cancer (HGSC)–derived organoids, and patient-derived xenografts (PDXs). Time-lapse tracking of ovarian cancer cells revealed that PGCCs primarily developed from endoreplication after exposure to sublethal concentrations of olaparib. PGCCs exhibited features of senescent cells but, after olaparib withdrawal, can escape senescence via restitutional multipolar endomitosis and other noncanonical modes of cell division to generate mitotically competent resistant daughter cells. The contraceptive drug mifepristone blocked PGCC formation and daughter cell formation. Mifepristone/olaparib combination therapy substantially reduced tumor growth in PDX models without previous olaparib exposure, while mifepristone alone decreased tumor growth in PDX models with acquired olaparib resistance. Thus, targeting PGCCs may represent a promising approach to potentiate the therapeutic response to PARPi and overcome PARPi-induced resistance.