according to a proteogenomic study.
Further insights into the regulatory mechanisms of the disease were also identified, based on findings from genome-wide phosphoproteome and acetylome surveys.
“This study provides a comprehensive overview of the molecular systems of endometrial carcinoma at the genomic, transcriptomic, and proteomic levels,” wrote Yongchao Dou, PhD, of Baylor College of Medicine, Houston, and colleagues. The findings were published in Cell.
The researchers prospectively analyzed proteogenomic data from 95 endometrial carcinoma tumors, including 83 endometrioid and 12 serous samples, and 49 nonmalignant tissue samples. Whole genome and exome, DNA methylation, and total and microRNA sequencing analyses were performed for each sample.
An integrated evaluation of proteins, posttranslational modifications (phosphorylation and acetylation), DNA, and RNA were used to detect novel regulatory mechanisms and potential therapeutic targets.
The researchers confirmed previous data on the impact of gain-of-function TP53 mutations on the Aurora kinase pathway, notably the relationship between AURKA expression and negative outcomes in endometrial carcinoma.
“[These findings] provide a theoretical basis for the use of AURKA inhibitors in these tumors,” the researchers wrote.
In addition, the team found evidence of a new regulatory pathway involving ESRP2, circular RNA (circRNA), and QKI, each of which plays a key role in regulatory function.
“Through its known function in isoform regulation, ESRP2 could also directly regulate circRNA levels, and, if so, it could compete with QKI in circRNA-mediated gene regulation,” the researchers wrote.
Furthermore, they identified several gene products that could play a role in optimizing selection of patients for checkpoint blockade immunotherapy. One product in particular, CDK12, may better clinical response rates to immune checkpoint blockade.
The researchers also found evidence to suggest that measuring tumor antigen presentation defects could be more effective than measuring tumor mutation burden when selecting immunotherapy for patients with endometrial carcinoma.
“Although the results presented herein are predominantly observational, they provide the basis for multiple hypotheses of clinical relevance that can and should be further explored,” the researchers concluded.
The study was funded by the National Cancer Institute, the Cancer Prevention & Research Institutes of Texas, and the Robert and Janice McNair Foundation. The authors reported having no conflicts of interest.
SOURCE: Dou Y et al. Cell. 2020 Feb 13. doi: 10.1016/j.cell.2020.01.026.