CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas.

Missense mutations in exon 3 of , the gene encoding β-catenin, are associated with poor outcomes in endometrial carcinomas (EC). Clinically, mutation status has been difficult to use as a predictive biomarker as β-catenin oncogenic activity is modified by other factors, and these determinants are unknown. Here we reveal that CD73 restrains the oncogenic activity of exon 3 β-catenin mutants, and its loss associates with recurrence.

Mitochondrial defects and metabolic vulnerabilities in Lynch syndrome-associated MSH2-deficient endometrial cancer.

Unlabelled: Lynch syndrome (LS) is defined by inherited mutations in DNA mismatch repair genes, including and carries 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, specific mechanisms for LS-associated endometrial carcinogenesis are not well understood. Here, we assessed the effects of MSH2 loss on EC pathogenesis using a novel mouse model (PR-Cre , abbreviated Msh2KO), primary cell lines established from this model, human tissues, and human EC cell lines with isogenic MSH2 knockdown.

Context-dependent environmental associations with endometrial cancer histotype and genotype.

Objective: MLH1 loss due to methylation, detected during Lynch syndrome screening, is one of the most common molecular changes in endometrial cancer. It is well established that environmental influences such as nutritional state can impact gene methylation, both in the germline and in a tumor. In colorectal cancer and other cancer types, aging is associated with changes in gene methylation.

Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors.

Unlabelled: Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors.

MIG-6 Is Critical for Progesterone Responsiveness in Human Complex Atypical Hyperplasia and Early-Stage Endometrial Cancer.

Women with complex atypical hyperplasia (CAH) or early-stage endometrioid endometrial cancer (EEC) are candidates for fertility preservation. The most common approach is progesterone (P4) therapy and deferral of hysterectomy until after completion of childbearing. However, P4 therapy response rates vary, and molecular mechanisms behind P4 resistance are poorly understood.

Mechanisms of mutant β-catenin in endometrial cancer progression.

Endometrial carcinoma (EC) is the most diagnosed gynecological malignancy in Western countries. Both incidence and mortality rates of EC have steadily risen in recent years. Despite generally favorable prognoses for patients with the endometrioid type of EC, a subset of patients has been identified with decreased progression-free survival.

DNA Damage Repair Classifier Defines Distinct Groups in Hepatocellular Carcinoma.

DNA repair pathways have been associated with variability in hepatocellular carcinoma (HCC) clinical outcomes, but the mechanism through which DNA repair varies as a function of liver regeneration and other HCC characteristics is poorly understood. We curated a panel of 199 genes representing 15 DNA repair pathways to identify DNA repair expression classes and evaluate their associations with liver features and clinicopathologic variables in The Cancer Genome Atlas (TCGA) HCC study. We identified two groups in HCC, defined by low or high expression across all DNA repair pathways.

Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer.

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.

Objective.

Simple, accurate calculation of mechanical power in pressure controlled ventilation (PCV).

Background: Mechanical power is a promising new metric to assess energy transfer from a mechanical ventilator to a patient, which combines the contributions of multiple parameters into a single comprehensive value. However, at present, most ventilators are not capable of calculating mechanical power automatically, so there is a need for a simple equation that can be used to estimate this parameter at the bedside. For volume-controlled ventilation (VCV), excellent equations exist for calculating power from basic ventilator parameters, but for pressure-controlled ventilation (PCV), an accurate, easy-to-use equation has been elusive.

Adjuvant treatment in early-stage endometrial cancer: context-dependent impact of somatic mutation on recurrence-free survival.

Objective: The primary objective of this study was to determine whether women whose tumors harbor a somatic mutation have longer recurrence-free survival if they receive traditional adjuvant therapy strategies compared with those who do not.

Methods: A retrospective, stage I endometrial cancer cohort from MD Anderson Cancer Center was assessed. Clinical and pathological characteristics and type of adjuvant therapy (cuff brachytherapy, pelvic radiation, chemotherapy) were obtained by review of medical records.

A phase II study of MK-2206, an AKT inhibitor, in uterine serous carcinoma.

Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC.

Differences in the microbial profiles of early stage endometrial cancers between Black and White women.

Objective: Black women suffer a higher mortality from endometrial cancer (EC) than White women. Potential biological causes for this disparity include a higher prevalence of obesity and more lethal histologic/molecular subtypes. We hypothesize that another biological factor driving this racial disparity could be the EC microbiome.

The Changing Landscape of Gynecologic Cancer Mortality in the United States.

Uterine corpus cancer mortality is now similar to that for ovarian cancer, and the disproportionate burden among Black women is widening.

Mechanical Power: A New Concept in Mechanical Ventilation.

Mechanical ventilation is a potentially life-saving therapy for patients with acute lung injury, but the ventilator itself may cause lung injury. Ventilator-induced lung injury (VILI) is sometimes an unfortunate consequence of mechanical ventilation. It is not clear however how best to minimize VILI through adjustment of various parameters including tidal volume, plateau pressure, driving pressure, and positive end expiratory pressure (PEEP).

Inactivating Mutations of the Gene Weaken Ku80/Ku70-Mediated DNA Repair and Sensitize Endometrial Cancer to Chemotherapy.

IK is a mitotic factor that promotes cell cycle progression. Our previous investigation of 271 endometrial cancer (EC) samples from the Cancer Genome Atlas (TCGA) dataset showed IK somatic mutations were enriched in a cluster of patients with high-grade and high-stage cancers, and this group had longer survival. This study provides insight into how IK somatic mutations contribute to EC pathophysiology.

Clinical and Financial Implications of Second-Opinion Surgical Pathology Review.

Objectives: Second-opinion pathology review identifies clinically significant diagnostic discrepancies for some patients. Discrepancy rates and laboratory-specific costs in a single health care system for patients referred from regional affiliates to a comprehensive cancer center ("main campus") have not been reported.

Methods: Main campus second-opinion pathology cases for 740 patients from eight affiliated hospitals during 2016 to 2018 were reviewed.

Long-term Patterns of Excess Mortality among Endometrial Cancer Survivors.

Background: We investigated excess mortality after endometrial cancer using conditional relative survival estimates and standardized mortality ratios (SMR).

Methods: Women diagnosed with endometrial cancer during 2000-2017 ( = 183,153) were identified in the Surveillance Epidemiology and End Results database. SMRs were calculated as observed deaths among endometrial cancer survivors over expected deaths among demographically similar women in the general U.

Loss of CD73 shifts transforming growth factor-β1 (TGF-β1) from tumor suppressor to promoter in endometrial cancer.

In many tumors, CD73 (NT5E), a rate-limiting enzyme in adenosine biosynthesis, is upregulated by TGF-β and drives tumor progression. Conversely, CD73 is downregulated in endometrial carcinomas (EC) despite a TGF-β-rich environment. Through gene expression analyses of normal endometrium samples of the uterine cancer TCGA data set and genetic and pharmacological studies, we discovered CD73 loss shifts TGF-β1 from tumor suppressor to promoter in EC.

Clinical significance of homologous recombination deficiency score testing in endometrial Cancer.

Background: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer.

Methods: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay.