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Multi-Omic Endometrial Cancer Study Reveals Novel Pathways, Treatment Targets

NEW YORK – Researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC), New York University School of Medicine, Baylor College of Medicine, Washington University in St. Louis, Pacific Northwest National Laboratory, and elsewhere have published a detailed proteogenomic analysis of endometrial cancer, revealing new pathways of potential mechanistic importance in disease development and possible novel treatment targets.

In a study published in Cell on Thursday, the researchers described their characterization of 95 prospectively collected endometrial carcinomas and 49 normal tissues, comprising 83 endometrioid and 12 serous tumors. Their analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circular RNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways.

"An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation," the authors wrote. "We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions."

For their study, the researchers performed whole-exome, whole-genome, and total and miRNA sequencing on each tumor and normal sample, along with DNA methylation analyses. They also quantified the relative levels of the proteins and post-translational modification (PTM) sites across the samples.

The tumors were classified into four genomic subtypes that had previously been outlined in a 2013 TCGA endometrial cancer landmark study: POLE, a rare ultramutated subtype with endometrioid histology and good prognosis; microsatellite instability (MSI), a hypermutated endometrioid subtype; copy-number (CNV) low, which consists of most of the rest of the endometrioid cases; and CNV-high, comprised of all serous and the most aggressive endometrioid cancers.

The cohort included seven POLE, 25 MSI, 43 CNV-low, and 20 CNV-high tumors. Protein and PTM levels differed between genomic subtypes, the researchers noted. A functional analysis of protein levels by subtype indicated a relative downregulation of cell cycle proteins and phosphorylation in the CNV-low subtype, associated with an increase in cell transport and metabolism proteins. Further, phosphorylation on proteins related to DNA double-strand break repair was decreased without a corresponding protein level change.

Conversely, the CNV-high subtype had increased phosphorylation on proteins involved in ATM signaling. Also, mismatch repair was generally suppressed in POLE, MSI, and CNV-high subtypes, and serous samples had the highest upregulation of ribosome biogenesis, which has been associated with poor cancer prognosis.

About 61 percent of all somatic mutations were found in the seven POLE tumors, while the MSI tumors carried 88 percent of all indels in the cohort. Additionally, the researchers identified INPPL1, KMT2B, and JAK1 as putative significantly mutated genes (SMGs) in the MSI subtype, which were not reported in the TCGA study.

In another analysis, the researchers looked at TP53 mutations, finding them in 23 tumors in the cohort, including all serous carcinomas. Rather than grouping all TP53-mutated tumors together and looking for a single molecular phenotype, they segregated them by mutation type and location and identified several proteomic and phosphoproteomic signatures.

The researchers also compared proteomic and transcriptomic changes between the cancer subtypes. They generated a score for each sample based on the DNA damage response (DDR) marker phosphoproteins and found that DDR-high samples were enriched for serous tumors and therefore the CNV-high subtype, but that DDR-high endometrioid tumors came from the CNV-high, POLE, and MSI genomic subgroups. This indicated that active DNA damage signaling is largely independent of genomic subtype.

"Integrating comprehensive quantitative measurements of protein, phosphorylation, and acetylation with genomic and transcriptomic measurements not only has provided novel insights into fundamental biological processes associated with carcinogenesis but also has provided intriguing leads for new therapeutic approaches in [endometrial cancer], including potential criteria for selecting the most appropriate therapies," the authors wrote.