TY - JOUR
T1 - Obesity and altered angiogenic-related gene expression in endometrial cancer
AU - Cobb, Lauren Patterson
AU - Siamakpour-Reihani, Sharareh
AU - Zhang, Dadong
AU - Qin, Xiaodi
AU - Owzar, Kouros
AU - Zhou, Chunxiao
AU - Conrads, Thomas P.
AU - Maxwell, G. Larry
AU - Darcy, Kathleen M.
AU - Bateman, Nicholas W.
AU - Litzi, Tracy
AU - Bae-Jump, Victoria
AU - Secord, Angeles Alvarez
N1 - Funding Information:
As Duke Cancer Institute members, we acknowledge support from the Duke Cancer Institute as part of the P30 Cancer Center Support Grant (Grant ID: P30 CA014236), specifically the Duke Cancer Institute 's Bioinformatics Shared Resource. This work was also supported by the Charles B. Hammond Research Fund through the Duke University Department of Obstetrics and Gynecology. Additionally, this study was suppported in part by the U. S. Department of Defense - Uniformed Services University of the Health Sciences ( HU0001-16-2-0006 and HU0001-16-2-0014 ).
Publisher Copyright:
© 2021
PY - 2021/11
Y1 - 2021/11
N2 - Objectives: Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression. Methods: We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1fl/flp53fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq. Results: At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342). Conclusions: Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.
AB - Objectives: Evaluate association between obesity and angiogenic-related gene expression in endometrial cancer (EC). Evaluate interaction between diet and metformin on angiogenic-related gene expression. Methods: We evaluated the association between 168 human angiogenic-related genes and body mass index (BMI) in the TCGA Uterine Corpus Endometrial Carcinoma cohort (endometrioid endometrial cancer (EEC) cohort n = 290, and copy number high cohort n = 55), an independent validation cohort from Gynecologic Cancer Center of Excellence (GYN-COE) (n = 62) and corresponding 185 homologous mouse genes in an LKB1fl/flp53fl/fl mouse model of EC (n = 20). Mice received 60% of calories from fat in a high-fat diet (HFD), mimicking diet-induced obesity, versus 10% of calories from fat in a low-fat diet (LFD). After tumor growth, HFD (n = 5) and LFD (n = 5) mice were treated with metformin (200 mg/kg/day) or control. Whole transcriptome analysis of mouse tumors was performed using RNA-Seq. Results: At a false-discovery rate of 10%, twenty-one angiogenic-related genes were differentially expressed with respect to BMI when adjusting for grade in the TCGA EEC cohort. Evaluation of these genes in the mouse model control group revealed association between increased Edil3 expression in HFD versus LFD mice (2.5-fold change (FC); unadjusted p = 0.03). An interaction was observed for expression of Edil3 between diet and metformin treatment (unadjusted p = 0.009). Association between BMI and increased expression of EDIL3 was validated in one of four EDIL3 probesets in the GYN-COE cohort (p = 0.0011, adjusted p = 0.0342). Conclusions: Obesity may promote tumor progression via differential modulation of angiogenic pathways in EEC. Our exploratory findings demonstrated that EDIL3 may be a candidate gene of interest.
KW - Angiogenesis
KW - Endometrial cancer
KW - Gene expression
KW - Metformin
KW - Obesity
UR - http://www.scopus.com/inward/record.url?scp=85115016513&partnerID=8YFLogxK
U2 - 10.1016/j.ygyno.2021.08.010
DO - 10.1016/j.ygyno.2021.08.010
M3 - Article
C2 - 34538531
AN - SCOPUS:85115016513
SN - 0090-8258
VL - 163
SP - 320
EP - 326
JO - Gynecologic Oncology
JF - Gynecologic Oncology
IS - 2
ER -