A comprehensive genome-wide cross-trait analysis of sexual factors and uterine leiomyoma.

Age at first sexual intercourse (AFS) and lifetime number of sexual partners (NSP) may influence the pathogenesis of uterine leiomyoma (UL) through their associations with hormonal concentrations and uterine infections. Leveraging summary statistics from large-scale genome-wide association studies conducted in European ancestry for each trait (NAFS = 214,547; NNSP = 370,711; NUL = 302,979), we observed a significant negative genomic correlation for UL with AFS (rg = -0.11, P = 7.83×10-4), but not with NSP (rg = 0.01, P = 0.62). Four specific genomic regions were identified as contributing significant local genetic correlations to AFS and UL, including one genomic region further identified for NSP and UL. Partitioning SNP-heritability with cell-type-specific annotations, a close clustering of UL with both AFS and NSP was identified in immune and blood-related components. Cross-trait meta-analysis revealed 15 loci shared between AFS/NSP and UL, including 7 novel SNPs. Univariable two-sample Mendelian randomization (MR) analysis suggested no evidence for a causal association between genetically predicted AFS/NSP and risk of UL, nor vice versa. Multivariable MR adjusting for age at menarche or/and age at natural menopause revealed a significant causal effect of genetically predicted higher AFS on a lower risk of UL. Such effect attenuated to null when age at first birth was further included. Utilizing participant-level data from the UK Biobank, one-sample MR based on genetic risk scores yielded consistent null findings among both pre-menopausal and post-menopausal females. From a genetic perspective, our study demonstrates an intrinsic link underlying sexual factors (AFS and NSP) and UL, highlighting shared biological mechanisms rather than direct causal effects. Future studies are needed to elucidate the specific mechanisms involved in the shared genetic influences and their potential impact on UL development.

Uterine Leiomyomas with Specific Histology Features of Two Fumarate Hydratase/Succinate Dehydrogenase-Deficient Tumors: A Double Case Report.

Background and Objectives: Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH) give rise to various familial cancer syndromes, with these alterations being characteristic of certain types of histomorphologically specific leiomyomas that hold significant predictive value. Materials and Methods: This study presents two cases of uterine leiomyomas exhibiting rare histomorphological and genetic characteristics, which are crucial for prognosis and further treatment. Results: Distinct histopathological features such as marked nuclear atypia, intracellular eosinophilic globules, and abnormal intratumoral vessels raise suspicion for specific leiomyoma subtypes, which carry predictive significance for additional hereditary cancer syndromes. Immunohistochemical analysis confirmed FH/SDH deficiency in both patients, who underwent careful follow-up. Conclusions: This study describes two cases involving unusual leiomyomas, the histopathological characteristics of which may easily go unrecognized. These features hold predictive significance because their specific mutations point to additional hereditary cancer syndromes, highlighting the need for further examinations.

Uterine leiomyoma causes an increase in systolic blood pressure: a two-sample Mendelian randomization study.

Objectives: Hypertension and hypertensive disorders of pregnancy (HDP) are common diseases in women at different stages, which affect women's physical and mental health, and the impact of the latter on the offspring cannot not be ignored. Observational studies have investigated the correlation between uterine leiomyoma (UL) and the above conditions, but the relationship remains unclear. In this study, we employed two-sample Mendelian randomization (MR) analysis to assess the association between UL and hypertension, HDP, as well as blood pressure. Methods: We collected genetic association data of UL (35,474 cases), hypertension (129,909 cases), HDP (gestational hypertension with 8,502 cases, pre-eclampsia with 6,663 cases and eclampsia with 452cases), systolic blood pressure (SBP) and diastolic blood pressure (DBP) (both 757,601 participants) from published available genome-wide association studies (GWAS). The single nucleotide polymorphisms (SNPs) associated with UL phenotype were used as instrumental variables, and hypertension, three sub-types of HDP, SBP and DBP were used as outcomes. The inverse-variance weighted (IVW) method was employed as the primary method of causal inference. Heterogeneity was assessed using Cochran's Q test, and sensitivity analyses were conducted using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) tests to evaluate the pleiotropy of instrumental variables. PhenoScanner search was used to remove confounding SNP. Robustness and reliability of the results were assessed using methods such as the weighted median and weighted mode. Results: The IVW analysis revealed a positive correlation between genetically predicted UL and SBP [odds ratio (OR)= 1.67, 95% confidence interval (CI):1.24~2.25, P = 0.0007], and no statistical association was found between UL and hypertension, HDP, or DBP. The MR-Egger regression suggested that the above causal relationships were not affected by horizontal pleiotropy. The weighted median method and weighted model produced similar results to the IVW. Conclusion: Based on large-scale population GWAS data, our MR analysis suggested a causal relationship between UL and SBP. Therefore, women with UL, especially pregnant women, should pay attention to monitoring their blood pressure levels. For patients with hypertension who already have UL, interventions for UL may serve as potential therapeutic methods for managing blood pressure.

Genetic Mechanisms Driving Uterine Leiomyoma Pathobiology, Epidemiology, and Treatment.

Uterine leiomyomas (ULs) are the most common benign tumor of the uterus. They can be associated with symptoms including abnormal uterine bleeding, pelvic pain, urinary frequency, and pregnancy complications. Despite the high prevalence of UL, its underlying pathophysiology mechanisms have historically been poorly understood. Several mechanisms of pathogenesis have been suggested, implicating various genes, growth factors, cytokines, chemokines, and microRNA aberrations. The purpose of this study is to summarize the current research on the relationship of genetics with UL. Specifically, we performed a literature review of published studies to identify how genetic aberrations drive pathophysiology, epidemiology, and therapeutic approaches of UL. With regards to pathophysiology, research has identified MED12 mutations, HMGA2 overexpression, fumarate hydratase deficiency, and cytogenetic abnormalities as contributors to the development of UL. Additionally, epigenetic modifications, such as histone acetylation and DNA methylation, have been identified as contributing to UL tumorigenesis. Specifically, UL stem cells have been found to contain a unique DNA methylation pattern compared to more differentiated UL cells, suggesting that DNA methylation has a role in tumorigenesis. On a population level, genome-wide association studies (GWASs) and epidemiologic analyses have identified 23 genetic loci associated with younger age at menarche and UL growth. Additionally, various GWASs have investigated genetic loci as potential drivers of racial disparities in UL incidence. For example, decreased expression of Cytohesin 4 in African Americans has been associated with increased UL risk. Recent studies have investigated various therapeutic options, including ten-eleven translocation proteins mediating DNA methylation, adenovirus vectors for drug delivery, and "suicide gene therapy" to induce apoptosis. Overall, improved understanding of the genetic and epigenetic drivers of UL on an individual and population level can propel the discovery of novel therapeutic options.

Single-nucleotide polymorphism array and fluorescence in situ hybridization analysis to decode the cytogenetic profile of atypical partial hydatidiform moles diagnosed by short tandem repeat polymorphism analysis.

Accurate diagnosis of partial hydatidiform moles (PHMs) is crucial for improving outcomes of gestational trophoblastic neoplasia. The use of short tandem repeat (STR) polymorphism analysis to distinguish between PHM and hydropic abortuses is instrumental; however, its diagnostic power has not been comprehensively assessed. Herein, we evaluated the diagnostic efficacy of STR in differentiating between PHM and hydropic abortus, thus providing an opportunity for early measurement of human chorionic gonadotropin for PHMs. We reviewed charts of STR polymorphism analysis performed on fresh villous specimens and patient blood samples using a commercial kit for 16 loci. The genetic classification of 79 PHMs was confirmed. STR was reliable in differentiating PHMs when at least 15 loci were available. Typically, PHMs are characterized by their triploidy, including two paternal and one maternal haploid contribution. In our sample, seven PHMs lacked the three-allelic loci, requiring fluorescence in situ hybridization (FISH) analysis to investigate imbalanced biparental conceptus and single-nucleotide polymorphism array analysis to reveal cytogenetic details. Of these PHMs, two, three, and one were identified as androgenetic/biparental mosaics (diploids), monospermic diandric monogynic triploids, and a typical dispermic diandric monogynic triploid, respectively. The remaining case was monospermic origin, but its ploidy details could not be available. Therefore, STR differentiated PHM from a biparental diploid abortus in most cases. However, PHM diagnosis may be compromised when STR is used as the sole method for cases displaying distinct cytogenetic patterns lacking the three-allelic loci, including androgenetic/biparental mosaicism. Therefore, FISH should be considered to confirm the diagnosis.

Germline and Somatic Fumarate Hydratase Testing in Atypical Uterine Leiomyomata.

Women with germline pathogenic variants (PV) in the fumarate hydratase (FH) gene develop cutaneous and uterine leiomyomata and have an increased risk of developing aggressive renal cell carcinomas. Many of these women are unaware of their cancer predisposition until an atypical uterine leiomyoma is diagnosed during a myomectomy or hysterectomy, making a streamlined genetic counseling process after a pathology-based atypical uterine leiomyoma diagnosis critical. However, the prevalence of germline pathogenic/likely PVs in FH among atypical uterine leiomyomata cases is unknown. To better understand FH germline PV prevalence and current patterns of genetic counseling and germline genetic testing, we undertook a retrospective review of atypical uterine leiomyomata cases at a single large center. We compared clinical characteristics between the FH PV, FH wild-type (WT), and unknown genetic testing cohorts. Of the 144 cases with atypical uterine leiomyomata with evaluable clinical data, only 49 (34%) had documented genetic test results, and 12 (8.3%) had a germline FH PV. There were 48 IHC-defined FH-deficient cases, of which 41 (85%) had FH testing and nine had a germline FH PV, representing 22% of the tested cohort and 18.8% of the FH-deficient cohort. Germline FH PVs were present in 8.3% of evaluable patients, representing 24.5% of the cohort that completed genetic testing. These data highlight the disconnect between pathology and genetic counseling, and help to refine risk estimates that can be used when counseling patients with atypical uterine leiomyomata. PREVENTION RELEVANCE: Women diagnosed with fumarate hydratase (FH)-deficient uterine leiomyomata are at increased risk of renal cancer. This work suggests a more standardized pathology-genetic counseling referral pathway for these patients, and that research on underlying causes of FH-deficient uterine leiomyomata in the absence of germline FH pathogenic/likely pathogenic variants is needed.

Senescence-associated secretory phenotype (SASP) and uterine fibroids: Association with PD-L1 activation and collagen deposition.

Uterine fibroids (or uterine leiomyoma, UFs) are one of the most prevalent benign uterine tumors with high proliferation and collagen synthesis capabilities. UFs are a significant worldwide health issue for women, affecting their physical and financial well-being. Risk factors for UFs include age, racial disparities, obesity, uterine infections, hormonal variation, and lifestyle (i.e., diet, exercise, stress, and smoking). Senescence and its associated secretory phenotypes (SASPs) are among the most salient changes accompanying the aging process. As a result, SASPs are suggested to be one of the major contributors to developing UFs. Interleukin 6 (IL-6), IL-8, IL-1, chemokine ligand 20 (CCL-20), and transforming growth factor-beta (TGF-ß) are the most prominent SASPs associated with aging. In addition, different processes contribute to UFs such as collagen deposition and the changes in the immune microenvironment. Programmed death ligand 1 is a major player in the tumor immune microenvironment, which helps tumor cells evade immune attacks. This review focuses on the correlation of SASPs on two axes of tumor progression: immune suppression and collagen deposition. This review opens the door towards more investigations regarding changes in the UF immune microenvironment and age-UFs correlation and thus, a novel targeting approach for UF treatment.

Segregation, immunohistochemical, molecular and functional analyses classify a novel missense variant in fumarate hydratase (FH) as pathogenic.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant cancer predisposition syndrome characterized by cutaneous leiomyomas, uterine leiomyomas, and aggressive renal cancer. Germline variants in the fumarate hydratase (FH) gene predispose to HLRCC. Identifying germline pathogenic FH variants enables lifetime renal cancer screening and genetic testing for family members. In this report, we present a FH missense variant (c.1039T>C (p.S347P)), initially classified as a variant of uncertain significance. Clinical assessment, histopathological findings, molecular genetic studies, and enzymatic activity studies support the re-classification of the FH c.1039T>C variant to "pathogenic" based on ACMG/AMP criteria. Further insights into pathological recognition of FH-deficient renal cancer are discussed and should be recognized. This study has shown how (a) detailed multi-disciplinary analyses of a single variant can reclassify rare missense variants in FH and (b) careful pathological review of renal cancers is obligatory when HLRCC is suspected.

E2F transcription factor-1 modulates expression of glutamine metabolic genes in mouse embryonic fibroblasts and uterine sarcoma cells.

Metabolic reprogramming is considered as a hallmark of cancer and is clinically exploited as a novel target for therapy. The E2F transcription factor-1 (E2F1) regulates various cellular processes, including proliferative and metabolic pathways, and acts, depending on the cellular and molecular context, as an oncogene or tumor suppressor. The latter is evident by the observation that E2f1-knockout mice develop spontaneous tumors, including uterine sarcomas. This dual role warrants a detailed investigation of how E2F1 loss impacts metabolic pathways related to cancer progression. Our data indicate that E2F1 binds to the promoter of several glutamine metabolism-related genes. Interestingly, the expression of genes in the glutamine metabolic pathway were increased in mouse embryonic fibroblasts (MEFs) lacking E2F1. In addition, we confirm that E2f1-/- MEFs are more efficient in metabolizing glutamine and producing glutamine-derived precursors for proliferation. Mechanistically, we observe a co-occupancy of E2F1 and MYC on glutamine metabolic promoters, increased MYC binding after E2F1 depletion and that silencing of MYC decreased the expression of glutamine-related genes in E2f1-/- MEFs. Analyses of transcriptomic profiles in 29 different human cancers identified uterine sarcoma that showed a negative correlation between E2F1 and glutamine metabolic genes. CRISPR/Cas9 knockout of E2F1 in the uterine sarcoma cell line SK-UT-1 confirmed elevated glutamine metabolic gene expression, increased proliferation and increased MYC binding to glutamine-related promoters upon E2F1 loss. Together, our data suggest a crucial role of E2F1 in energy metabolism and metabolic adaptation in uterine sarcoma cells.

FOXO3a deregulation in uterine smooth muscle tumors.

OBJECTIVE: The present study aimed to investigate FOXO3a deregulation in Uterine Smooth Muscle Tumors (USMT) and its potential association with cancer development and prognosis. METHODS: The authors analyzed gene and protein expression profiles of FOXO3a in 56 uterine Leiomyosarcomas (LMS), 119 leiomyomas (comprising conventional and unusual leiomyomas), and 20 Myometrium (MM) samples. The authors used techniques such as Immunohistochemistry (IHC), FISH/CISH, and qRT-PCR for the present analyses. Additionally, the authors conducted an in-silico analysis to understand the interaction network involving FOXO3a and its correlated genes. RESULTS: This investigation revealed distinct expression patterns of the FOXO3a gene and protein, including both normal and phosphorylated forms. Expression levels were notably elevated in LMS, and Unusual Leiomyomas (ULM) compared to conventional Leiomyomas (LM) and Myometrium (MM) samples. This upregulation was significantly associated with metastasis and Overall Survival (OS) in LMS patients. Intriguingly, FOXO3a deregulation did not seem to be influenced by EGF/HER-2 signaling, as there were minimal levels of EGF and VEGF expression detected, and HER-2 and EGFR were negative in the analyzed samples. In the examination of miRNAs, the authors observed upregulation of miR-96-5p and miR-155-5p, which are known negative regulators of FOXO3a, in LMS samples. Conversely, the tumor suppressor miR-let7c-5p was downregulated. CONCLUSIONS: In summary, the outcomes of the present study suggest that the imbalance in FOXO3a within Uterine Smooth Muscle Tumors might arise from both protein phosphorylation and miRNA activity. FOXO3a could emerge as a promising therapeutic target for individuals with Unusual Leiomyomas and Leiomyosarcomas (ULM and LMS), offering novel directions for treatment strategies.

Uterine Leiomyosarcoma Associated With Perivascular Epithelioid Cell Tumor: A Phenomenon of Differentiation/Dedifferentiation and Evidence Suggesting Cell-of-Origin.

Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor thought to originate from perivascular epithelioid cells (PECs). The normal counterpart to PEC, however, has not been identified in any human organ, and the debate as to whether PEComa is related to smooth muscle tumors has persisted for many years. The current series characterizes 4 cases of uterine leiomyosarcoma (LMS) coexisting with PEComas. All cases exhibited an abrupt transition from the LMS to PEComa components. The LMS component displayed typical spindled morphology and fascicular growth pattern and was diffusely positive for desmin and smooth muscle myosin heavy chain, completely negative for HMB-45 and Melan A, and either negative or had focal/weak expression of cathepsin K and GPNMB. In contrast, the PEComa tumor cells in case 1 contained glycogen or lipid-distended cytoplasm with a foamy appearance (low grade), and in cases 2, 3, and 4, they displayed a similar morphology characterized by epithelioid cells with eosinophilic and granular cytoplasm and high-grade nuclear atypia. Different from the LMS component, the epithelioid PEComa cells in all cases were focally positive for HMB-45, and diffusely immunoreactive for cathepsin K and GPNMB. Melan A was focally positive in cases 1 and 3. Loss of fumarate hydratase expression (case 1) and RB1 expression (cases 2, 3, 4) was identified in both LMS and PEComa components, indicating that they are clonally related. In addition, both components showed an identical TP53 p.R196* somatic mutation and complete loss of p53 and ATRX expression in case 2 and complete loss of p53 expression in case 3. We hypothesize that LMSs containing smooth muscle progenitor cells may give rise to divergent, lineage-specific PEComatous lesions through differentiation or dedifferentiation. While we do not dispute the recognition of PEComas as a distinct entity, we advocate the hypothesis that modified smooth muscle cells represent the origin of a subset of PEComas, and our case series provides evidence to suggest this theory.

Genomic profile analysis of leiomyomas with bizarre nuclei and fumarate hydratase deficient leiomyomas: Strengths, weaknesses, and limitations of array-CGH interpretation.

A close relationship has been demonstrated between genomic complexity and clinical outcome in uterine smooth muscle tumors. We studied the genomic profiles by array-CGH of 28 fumarate hydratase deficient leiomyomas and 37 leiomyomas with bizarre nuclei (LMBN) from 64 patients. Follow-up was available for 46 patients (from three to 249 months, mean 87.3 months). All patients were alive without evidence of disease. For 51 array-CGH interpretable tumors the mean Genomic Index (GI) was 16.4 (median: 9.8; from 1 to 57.8), significantly lower than the mean GI in LMS (mean GI 51.8, p < 0.001). We described three groups: (1) a group with FH deletion (24/58) with low GI (mean GI: 11 vs. 22,4, p = 0.02), (2) a group with TP53 deletion (17/58) with higher GI (22.4 vs. 11 p = 0.02), and (3) a group without genomic events on FH or TP53 genes (17/58) (mean GI:18.3; from 1 to 57.8). Because none of these tumors recurred and none showed morphological features of LMS we concluded that GI at the cut-off of 10 was not applicable in these subtypes of LM. By integration of all those findings, a GI <10 in LMBN remains a valuable argument for benignity. Conversely, in LMBN a GI >10 or alteration in tumor suppressor genes, should not alone warrant a diagnosis of malignancy. Nine tumors were tested with Nanocind CINSARC® signature and all were classified in low risk of recurrence. We propose, based on our observations, a diagnostic approach of these challenging lesions.

Targeting Galectin 3 illuminates its contributions to the pathology of uterine serous carcinoma.

BACKGROUND: Uterine serous cancer (USC) comprises around 10% of all uterine cancers. However, USC accounts for approximately 40% of uterine cancer deaths, which is attributed to tumor aggressiveness and limited effective treatment. Galectin 3 (Gal3) has been implicated in promoting aggressive features in some malignancies. However, Gal3's role in promoting USC pathology is lacking. METHODS: We explored the relationship between LGALS3 levels and prognosis in USC patients using TCGA database, and examined the association between Gal3 levels in primary USC tumors and clinical-pathological features. CRISPR/Cas9-mediated Gal3-knockout (KO) and GB1107, inhibitor of Gal3, were employed to evaluate Gal3's impact on cell function. RESULTS: TCGA analysis revealed a worse prognosis for USC patients with high LGALS3. Patients with no-to-low Gal3 expression in primary tumors exhibited reduced clinical-pathological tumor progression. Gal3-KO and GB1107 reduced cell proliferation, stemness, adhesion, migration, and or invasion properties of USC lines. Furthermore, Gal3-positive conditioned media (CM) stimulated vascular tubal formation and branching and transition of fibroblast to cancer-associated fibroblast compared to Gal3-negative CM. Xenograft models emphasized the significance of Gal3 loss with fewer and smaller tumors compared to controls. Moreover, GB1107 impeded the growth of USC patient-derived organoids. CONCLUSION: These findings suggest inhibiting Gal3 may benefit USC patients.

Developing Novel Genomic Risk Stratification Models in Soft Tissue and Uterine Leiomyosarcoma.

PURPOSE: Leiomyosarcomas (LMS) are clinically and molecularly heterogeneous tumors. Despite recent large-scale genomic studies, current LMS risk stratification is not informed by molecular alterations. We propose a clinically applicable genomic risk stratification model. EXPERIMENTAL DESIGN: We performed comprehensive genomic profiling in a cohort of 195 soft tissue LMS (STLMS), 151 primary at presentation, and a control group of 238 uterine LMS (ULMS), 177 primary at presentation, with at least 1-year follow-up. RESULTS: In STLMS, French Federation of Cancer Centers (FNCLCC) grade but not tumor size predicted progression-free survival (PFS) or disease-specific survival (DSS). In contrast, in ULMS, tumor size, mitotic rate, and necrosis were associated with inferior PFS and DSS. In STLMS, a 3-tier genomic risk stratification performed well for DSS: high risk: co-occurrence of RB1 mutation and chr12q deletion (del12q)/ATRX mutation; intermediate risk: presence of RB1 mutation, ATRX mutation, or del12q; low risk: lack of any of these three alterations. The ability of RB1 and ATRX alterations to stratify STLMS was validated in an external AACR GENIE cohort. In ULMS, a 3-tier genomic risk stratification was significant for both PFS and DSS: high risk: concurrent TP53 mutation and chr20q amplification/ATRX mutations; intermediate risk: presence of TP53 mutation, ATRX mutation, or amp20q; low risk: lack of any of these three alterations. Longitudinal sequencing showed that most molecular alterations were early clonal events that persisted during disease progression. CONCLUSIONS: Compared with traditional clinicopathologic models, genomic risk stratification demonstrates superior prediction of clinical outcome in STLMS and is comparable in ULMS.

Clinical features and impact of p53 status on sporadic mismatch repair deficiency and Lynch syndrome in uterine cancer.

The clinical features of sporadic mismatch repair deficiency (MMRd) and Lynch syndrome (LS) in Japanese patients with endometrial cancer (EC) were examined by evaluating the prevalence and prognostic factors of LS and sporadic MMRd in patients with EC. Targeted sequencing of five LS susceptibility genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) was carried out in 443 patients with EC who were pathologically diagnosed with EC at the National Cancer Center Hospital between 2011 and 2018. Pathogenic variants in these genes were detected in 16 patients (3.7%). Immunohistochemistry for MMR proteins was undertaken in 337 of the 433 (77.9%) EC patients, and 91 patients (27.0%) showed absent expression of at least one MMR protein. The 13 cases of LS with MMR protein loss (93.8%) showed a favorable prognosis with a 5-year overall survival (OS) rate of 100%, although there was no statistically significant difference between this group and the sporadic MMRd group (p = 0.27). In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

Genetic and histological analysis intraplacental choriocarcinoma: a case report.

We report on single case of intraplacental choriocarcinoma (IC) coexisting with feto-maternal hemorrhage from our hospital, a rare malignant tumor that occurs in the chorionic villous trophoblast. To investigate genetic and epigenetic changes to the carcinogenesis of IC, we employed cancer gene panel analysis and whole methylation analysis from a recent case of IC. By Short Tandem Repeats analysis, we confirmed that the tumor of present IC was derived from concurrent normal chorionic villous trophoblast cells. No mutation was found in 145 cancer-related genes. Meanwhile, amplification in MDM2 gene was observed. Furthermore, we observed deferentially methylated CpG sites between tumor and surrounding normal placenta in present IC case. These observations suggest that IC might be arisen as a result of aberrations of methylation rather than of DNA mutations. Further studies are needed to clarify association between aberrant methylation and choriocarcinogenesis.

Psychosocial Stress and MicroRNA Expression Profiles in Myometrial Tissue of Women Undergoing Surgical Treatment for Uterine Fibroids.

Uterine leiomyomas (fibroids) are the most common non-cancerous tumors affecting women. Psychosocial stress is associated with fibroid risk and severity. The relationship between psychosocial stress and fibroid pathogenesis may involve alterations in microRNAs (miRNAs) although this has yet to be examined. We investigated associations between two psychosocial stress measures, a composite measure of recent stressful life events and perceived social status, with expression levels of 401 miRNAs in myometrium (n = 20) and fibroids (n = 44; 20 with paired fibroid and myometrium samples) among pre-menopausal women who underwent surgery for fibroid treatment. We used linear regressions to identify psychosocial stressors associated with miRNAs, adjusting for covariates (age, body mass index, race/ethnicity, and oral contraceptive use). The association between psychosocial stressors and miRNAs was considered statistically significant at an FDR p < 0.10 and showed a monotonic response (nominal p-trend < 0.05). In the myometrium, 21 miRNAs were significantly associated with a composite measure of recent stressful events, and two miRNAs were associated with perceived social status. No fibroid miRNAs were associated with either stress measure. Pathway analyses revealed miRNA-mRNA targets were significantly enriched (FDR p < 0.05) in pathways relevant to cancer/tumor development. Of the 74 differentially expressed miRNAs between myometrium and fibroids, miR-27a-5p and miR-301b were also associated with stress exposure. Our pilot analysis suggests that psychosocial stress is associated with myometrial miRNA expression and, thus, may have a role in the pathogenesis of fibroids from healthy myometrium.

The clinicopathologic and molecular features, and treatment outcome of fumarate hydratase-deficient renal cell carcinoma: a retrospective comparison with type 2 papillary renal cell carcinoma.

BACKGROUND: To compare clinicopathologic, molecular features, and treatment outcome between fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) and type 2 papillary renal cell carcinoma (T2 pRCC). METHODS: Data of T2 pRCC patients and FH-dRCC patients with additional next-generation sequencing information were retrospectively analyzed. The cancer-specific survival (CSS) and disease-free survival (DFS) were primary endpoint. RESULTS: A combination of FH and 2-succino-cysteine (2-SC) increased the rate of negative predictive value of FH-dRCC. Compared with T2 pRCC cases, FH-dRCC cases displayed a greater prevalence in young patients, a higher frequency of radical nephrectomy. Seven FH-dRCC and two T2 pRCC cases received systemic therapy. The VEGF treatment was prescribed most frequently, with an objective response rate (ORR) of 22.2% and a disease control rate (DCR) of 30%. A combined therapy with VEGF and checkpoint inhibitor reported an ORR of 40% and a DCR of 100%. FH-dRCC cases showed a shortened CSS (P = 0.042) and DFS (P < 0.001). The genomic sequencing revealed 9 novel mutations. CONCLUSIONS: Coupled with genetic detection, immunohistochemical biomarkers (FH and 2-SC) can distinguish the aggressive FH-dRCC from T2 pRCC. Future research is awaited to illuminate the association between the novel mutations and the clinical phenotypes of FH-dRCC in the disease progression.