The Molecular Effects of a High Fat Diet on Endometrial Tumour Biology

Michael Wilkinson; Piriyah Sinclair; Ludmilla Dellatorre-Teixeira; Patrick Swan; Eoin Brennan; Bruce Moran; Dirk Wedekind; Paul Downey; Kieran Sheahan; Emer Conroy; William M Gallagher; Neil Docherty; Carel le Roux; Donal J Brennan

doi:10.3390/life10090188

The Molecular Effects of a High Fat Diet on Endometrial Tumour Biology

Life (Basel). 2020 Sep 10;10(9):188. doi: 10.3390/life10090188.

Authors

Michael Wilkinson^{1

2}, Piriyah Sinclair², Ludmilla Dellatorre-Teixeira², Patrick Swan², Eoin Brennan², Bruce Moran³, Dirk Wedekind⁴, Paul Downey⁵, Kieran Sheahan³, Emer Conroy⁶, William M Gallagher⁶, Neil Docherty², Carel le Roux^{2

3}, Donal J Brennan^{1

2

6

7}

Affiliations

¹ Department of Gynaecological Oncology, UCD School of Medicine, Mater Misericordiae Universtity Hospital, Eccles Street, Dublin 7, D07 AX57 Dublin, Ireland.
² UCD Diabetes Complications Research Centre, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland.
³ Department of Pathology, St Vincent's University Hospital, Elm Park, Dublin 4, D04 YN63 Dublin, Ireland.
⁴ Biomedical Facility, Hanover Medical School, 30625 Hanover, Germany.
⁵ Department of Pathology, National Maternity Hospital, Holles Street, Dublin 2, D02 YH21 Dublin, Ireland.
⁶ Cancer Biology and Therapeutic Laboratory, UCD School of Biomolecular and Biomedical Science Ireland, UCD Conway Institute, University College Dublin, D14 NN96 Dublin, Ireland.
⁷ Systems Biology Ireland, UCD School of Medicine, Belfield, Dublin 4, D14 NN96 Dublin, Ireland.

Abstract

We sought to validate the BDII/Han rat model as a model for diet-induced obesity in endometrial cancer (EC) and determine if transcriptomic changes induced by a high fat diet (HFD) in an EC rat model can be used to identify novel biomarkers in human EC. Nineteen BDII/Han rats were included. Group A (n = 7) were given ad lib access to a normal calorie, normal chow diet (NCD) while Group B (n = 12) were given ad lib access to a calorie rich HFD for 15 months. RNAseq was performed on endometrial tumours from both groups. The top-ranking differentially expressed genes (DEGs) were examined in the human EC using The Cancer Genome Atlas (TCGA) to assess if the BDII/Han rat model is an appropriate model for human obesity-induced carcinogenesis. Weight gain in HFD rats was double the weight gain of NCD rats (50 g vs. 25 g). The incidence of cancer was similar in both groups (4/7-57% vs. 4/12-33%; p = 0.37). All tumours were equivalent to a Stage 1A, Grade 2 human endometrioid carcinoma. A total of 368 DEGs were identified between the tumours in the HFD group compared to the NCD group. We identified two upstream regulators of the DEGs, mir-33 and Brd4, and a pathway analysis identified downstream enrichment of the colorectal cancer metastasis and ovarian cancer metastasis pathways. Top-ranking DEGs included Tex14, A2M, Hmgcs2, Adamts5, Pdk4, Crabp2, Capn12, Npw, Idi1 and Gpt. A2M expression was decreased in HFD tumours. Consistent with these findings, we found a significant negative correlation between A2M mRNA expression levels and BMI in the TCGA cohort (Spearman's Rho = -0.263, p < 0.001). A2M expression was associated with improved overall survival (HR = 0.45, 95% CI 0.23-0.9, p = 0.024). Crabp2 expression was increased in HFD tumours. In human EC, CRABP2 expression was associated with reduced overall survival (HR = 3.554, 95% CI 1.875-6.753, p < 0.001). Diet-induced obesity can alter EC transcriptomic profiles. The BDII/Han rat model is a suitable model of diet-induced obesity in endometrial cancer and can be used to identify clinically relevant biomarkers in human EC.

Keywords: endometrial cancer; obesity; transcriptomics.