Exploitation of a Shared Genetic Signature Between Obesity and Endometrioid Endometrial Cancer

Overview

Journal Front Surg

Specialty General Surgery

Date 2023 Feb 10

PMID 36761027

Authors

Junyi Duan

Jiahong Yi

Yun Wang

Affiliations

Soon will be listed here.

Abstract

Aims: The findings in epidemiological studies suggest that endometrioid endometrial cancer (EEC) is associated with obesity. However, evidence from gene expression data for the relationship between the two is still lacking. The purpose of this study was to explore the merits of establishing an obesity-related genes (ORGs) signature in the treatment and the prognostic assessment of EEC.

Methods: Microarray data from GSE112307 were utilized to identify ORGs by using weighted gene co-expression network analysis. Based on the sequencing data from TCGA, we established the prognostic ORGs signature, confirmed its value as an independent risk factor, and constructed a nomogram. We further investigated the association between grouping based on ORGs signature and clinicopathological characteristics, immune infiltration, tumor mutation burden and drug sensitivity.

Results: A total of 10 ORGs were identified as key genes for the construction of the signature. According to the ORGs score computed from the signature, EEC patients were divided into high and low-scoring groups. Overall survival (OS) was shorter in EEC patients in the high-scoring group compared with the low-scoring group ( < 0.001). The results of the Cox regression analysis showed that ORGs score was an independent risk factor for OS in EEC patients (HR = 1.017, 95% confidence interval = 1.011-1.023; < 0.001). We further revealed significant disparities between scoring groups in terms of clinical characteristics, tumor immune cell infiltration, and tumor mutation burden. Patients in the low-scoring group may be potential beneficiaries of immunotherapy and targeted therapies.

Conclusions: The ORGs signature established in this study has promising prognostic predictive power and may be a useful tool for the selection of EEC patients who benefit from immunotherapy and targeted therapies.

References

Lu K, Broaddus R . Endometrial Cancer. N Engl J Med. 2020; 383(21):2053-2064. DOI: 10.1056/NEJMra1514010. View

Bhaskaran K, Douglas I, Forbes H, Dos-Santos-Silva I, Leon D, Smeeth L . Body-mass index and risk of 22 specific cancers: a population-based cohort study of 5·24 million UK adults. Lancet. 2014; 384(9945):755-65. PMC: 4151483. DOI: 10.1016/S0140-6736(14)60892-8. View

Almanza A, Mnich K, Blomme A, Robinson C, Rodriguez-Blanco G, Kierszniowska S . Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer. Nat Commun. 2022; 13(1):2493. PMC: 9076827. DOI: 10.1038/s41467-022-30159-0. View

Li S, Shi X, Chen M, Xu N, Sun D, Bai R . Angiogenin promotes colorectal cancer metastasis via tiRNA production. Int J Cancer. 2019; 145(5):1395-1407. DOI: 10.1002/ijc.32245. View

Khan F, Owusu-Tieku N, Dai X, Liu K, Wu Y, Tsai H . Wnt/β-Catenin Pathway-Regulated Fibromodulin Expression Is Crucial for Breast Cancer Metastasis and Inhibited by Aspirin. Front Pharmacol. 2019; 10:1308. PMC: 6886402. DOI: 10.3389/fphar.2019.01308. View

Wiegand K, Lee A, Al-Agha O, Chow C, Kalloger S, Scott D . Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J Pathol. 2011; 224(3):328-33. DOI: 10.1002/path.2911. View

Marabelle A, Le D, Ascierto P, Di Giacomo A, De Jesus-Acosta A, Delord J . Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019; 38(1):1-10. PMC: 8184060. DOI: 10.1200/JCO.19.02105. View

Yang W, Soares J, Greninger P, Edelman E, Lightfoot H, Forbes S . Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res. 2012; 41(Database issue):D955-61. PMC: 3531057. DOI: 10.1093/nar/gks1111. View

Chen W, Lu S, Yang C, Li N, Chen X, He J . Hyperinsulinemia restrains endometrial angiogenesis during decidualization in early pregnancy. J Endocrinol. 2019; 243(2):137-148. DOI: 10.1530/JOE-19-0127. View

10.

Ott P, Bang Y, Berton-Rigaud D, Elez E, Pishvaian M, Rugo H . Safety and Antitumor Activity of Pembrolizumab in Advanced Programmed Death Ligand 1-Positive Endometrial Cancer: Results From the KEYNOTE-028 Study. J Clin Oncol. 2017; 35(22):2535-2541. DOI: 10.1200/JCO.2017.72.5952. View

11.

Dao M, Sokolovska N, Brazeilles R, Affeldt S, Pelloux V, Prifti E . A Data Integration Multi-Omics Approach to Study Calorie Restriction-Induced Changes in Insulin Sensitivity. Front Physiol. 2019; 9:1958. PMC: 6371001. DOI: 10.3389/fphys.2018.01958. View

12.

Alshabi A, Vastrad B, Shaikh I, Vastrad C . Identification of Crucial Candidate Genes and Pathways in Glioblastoma Multiform by Bioinformatics Analysis. Biomolecules. 2019; 9(5). PMC: 6571969. DOI: 10.3390/biom9050201. View

13.

Yoshihara K, Shahmoradgoli M, Martinez E, Vegesna R, Kim H, Torres-Garcia W . Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013; 4:2612. PMC: 3826632. DOI: 10.1038/ncomms3612. View

14.

Kandoth C, Schultz N, Cherniack A, Akbani R, Liu Y, Shen H . Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497(7447):67-73. PMC: 3704730. DOI: 10.1038/nature12113. View

15.

Banerjee S, Moore K, Colombo N, Scambia G, Kim B, Oaknin A . Maintenance olaparib for patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021; 22(12):1721-1731. DOI: 10.1016/S1470-2045(21)00531-3. View

16.

Larsson S, Burgess S . Causal role of high body mass index in multiple chronic diseases: a systematic review and meta-analysis of Mendelian randomization studies. BMC Med. 2021; 19(1):320. PMC: 8672504. DOI: 10.1186/s12916-021-02188-x. View

17.

Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K . Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020; 21(10):1353-1365. DOI: 10.1016/S1470-2045(20)30445-9. View

18.

Ledinek Z, Sobocan M, Knez J . The Role of CTNNB1 in Endometrial Cancer. Dis Markers. 2022; 2022:1442441. PMC: 9072012. DOI: 10.1155/2022/1442441. View

19.

Wan Y, Beverley-Stevenson R, Carlisle D, Clarke S, Edmondson R, Glover S . Working together to shape the endometrial cancer research agenda: The top ten unanswered research questions. Gynecol Oncol. 2016; 143(2):287-293. DOI: 10.1016/j.ygyno.2016.08.333. View

20.

Maeser D, Gruener R, Huang R . oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform. 2021; 22(6). PMC: 8574972. DOI: 10.1093/bib/bbab260. View