Andrew F Olshan

Epigenetic mechanisms underlying endometrial cancer outcomes: race-specific patterns of DNA methylation associated with molecular subtypes and survival

Abstract Endometrial cancer (EC) is the fourth most common cancer in women in the USA. Stark racial disparities are present in EC outcomes in which Black women have significantly higher EC-related mortality than White women. The social and biologic factors that contribute to these disparities are complex and may include racial differences in epigenetic landscapes. To investigate race-specific epigenetic differences in EC tumor characteristics and outcomes, we utilized the most recent data within the Cancer Genome Atlas (TCGA). Genome-wide CpG methylation data for more than 850 000 CpG sites were analyzed across 245 tumor samples, including 52 from Black women and 181 from White women. Race-adjusted and race-stratified associations among CpG methylation in ECs and molecular subtypes and disease-free survival were examined. Race-specific analysis identified subtype-associated CpGs within 9572 genes in tumors from White women and only 10 genes in tumors that were from Black women. Race-specific analyses also identified survival-associated CpGs with 1119 unique genes identified in tumors from White women and none identified in tumors from Black women. Genes identified with differential methylation among subtypes included those involved in oxidative stress (HIF3A), and DNA repair (MLH1). Data from a replication cohort highlighted genes overlapping with those identified within the TCGA, such as G Protein Subunit Beta 1 (GNB1), involved in G-protein signaling, and Interleukin 37 (IL37), involved in cytokine signaling. Identification of these racial differences in EC tumor epigenetic landscapes and associated changes in gene expression may provide insight into strategies to improve outcomes and reduce disparities.

Adverse Urinary System Diagnoses among Older Women with Endometrial Cancer

Abstract Background: Endometrial cancer and its treatment may impact urinary system function, but few large-scale studies have examined urinary diagnoses among endometrial cancer survivors. We investigated the risk of several urinary outcomes among older women with endometrial cancer compared with similar women without a cancer history. Methods: Women aged 66+ years with an endometrial cancer diagnosis during 2004–2017 (N = 44,386) and women without a cancer history (N = 221,219) matched 1:5 on exact age, race/ethnicity, and state were identified in the Surveillance, Epidemiology, and End Results-Medicare linked data. ICD-9 and -10 diagnosis codes were used to define urinary outcomes in the Medicare claims. HRs for urinary outcomes were estimated using multivariable Cox proportional hazards regression models. Results: Relative to women without cancer, endometrial cancer survivors were at an increased risk of several urinary system diagnoses, including lower urinary tract infection [HR, 2.36; 95% confidence interval (CI), 2.32–2.40], urinary calculus (HR, 2.22; 95% CI, 2.13–2.31), renal failure (HR, 2.28; 95% CI, 2.23–2.33), and chronic kidney disease (HR, 1.85; 95% CI, 1.81–1.90). Similar associations were observed in sensitivity analyses limited to 1+ and 5+ years after endometrial cancer diagnosis. Black race, higher comorbidity index, higher stage or grade cancer, non-endometrioid histology, and treatment with chemotherapy and/or radiation were often significant predictors of urinary outcomes among endometrial cancer survivors. Conclusions: Our results suggest that, among older women, the risk of urinary outcomes is elevated after endometrial cancer. Impact: Monitoring for urinary diseases may be a critical part of long-term survivorship care for older women with an endometrial cancer history.