Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), results in a broad range of phenotypes. A recent study reported that DS cells show genome-wide transcriptional changes in which up- or down-regulated genes are clustered in gene expression dysregulation domains (GEDDs). GEDDs were also reported in fibroblasts derived from a DS mouse model duplicated for some Hsa21-orthologous genes, indicating cross-species conservation of this phenomenon. Here we investigate GEDDs using the Dp1Tyb mouse model of DS, which is duplicated for the entire Hsa21-orthologous region of mouse chromosome 16. Our statistical analysis shows that GEDDs are present both in DS cells and in Dp1Tyb mouse fibroblasts and hippocampus. However, we find that GEDDs do not depend on the DS genotype but occur whenever gene expression changes. We conclude that GEDDs are not a specific feature of DS but instead result from the clustering of co-regulated genes, a function of mammalian genome organisation.

Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival. Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression. Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases. Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis. Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.

Background: Obesity has been implicated in the progression of ovarian cancer, but associations between body mass index (BMI) and survival outcomes are mixed. Studies evaluating pre- or peri-diagnosis BMI have generally found associations between higher BMI and worse overall survival (OS), but studies with post-diagnosis BMI measures are limited. Furthermore, no existing post-diagnosis BMI and ovarian cancer survival studies have conducted analyses stratified by race. Objective: We undertook this study to characterize changes over time in BMI among ovarian cancer cases from the Vanderbilt University Medical Center (VUMC) and to evaluate associations in relation to overall survival (OS); differences by race were examined in stratified analyses. Methods: We assembled a retrospective cohort of Tumor Registry confirmed ovarian cancer cases from VUMC EMR. BMI (kg/m2) at diagnosis, and 6, 12, 18, and 24 months after diagnosis (±8 weeks) were used to classify obesity according to the World Health Organization (WHO) guidelines as underweight (<18.5), normal weight (<25), overweight (<30), or obese (≥30.0). BMI changes over time were determined by the ratio of the last to first available measure, and categorized as increased (>1.05%), decreased (<0.95), or stable (reference). Associations with OS were quantified by Hazard Ratios (HRs) and 95% Confidence Intervals (CIs) from Cox proportional-hazards regression in multivariable adjusted race-stratified analyses. Results: Among 380 ovarian cancer cases with peri- or post-diagnosis BMI measures available from EMR, the relative prevalence of WHO normal weight cases decreased over time (diagnosis: 40.4%; 6 months: 38.2%; 12 months: 35.5%; 18 months: 27.7%; 24 months: 22.8%); there were more cases who had a decreased BMI (46.6%) than increased BMI (28.4%). Neither the prevalence nor percent of patients with changes differed by race. Among Caucasians (86.8%), a BMI increase was associated with a decreased risk of death (HR: 0.62, 95% CI: 0.40-0.97) while a BMI decrease was associated with an increased risk of death (HR: 2.18, 95% CI: 1.51-3.17). However, this seemed to differ among African Americans (6.1%), where both an increased and decreased BMI tended to have worse OS. Conclusions: Changes in BMI after a diagnosis of ovarian cancer may have different associations with mortality by race. To further expand upon these preliminary findings, our next steps include conducting analysis with time-varying covariates and identifying collaborators with ovarian cancer cases who have post-diagnosis BMI measures available for additional analysis. Citation Format: Alicia Beeghly-Fadiel, Nneka J Anyanwu, Shyria Karam, Demetra Hufnagel, George Bukenya, Sara Duque, Deok Son, Andrew J Wilson, Marta A Crispens. Body mass index, race, and ovarian cancer: Characterizing changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C069.

Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship. Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis. Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94). Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed. Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3228.