Discovery of novel RNA transcripts for endometrial cancer with copy-number high alterations using pan-cancer analysis of whole genomes (PCAWG) endometrial cancer dataset (275)

Abstract

<b>Objectives:</b> Uterine serous carcinoma is an aggressive type of endometrial cancer that has a propensity for metastatic spread and disproportionately affects Black women. Several new drugs are being evaluated in clinical trials for uterine serous carcinoma, including trastuzumab, pembrolizumab - lenvatinib combination, and adavosertib. However, additional treatment options are greatly needed. The Cancer Genome Atlas (TCGA) endometrial cancer project has shown that endometrial cancer can be broadly divided into four molecular classifications. Within the four molecular subtypes, the copy-number high group consists of high-grade endometrioid carcinoma and uterine serous carcinoma, which are characterized by frequent <i>TP53</i> mutation and somatic copy number alterations. To better understand the biology of this aggressive subset of endometrial cancer, we have performed bioinformatic analysis using the dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and TCGA. <b>Methods:</b> To better understand the biology of uterine serous carcinoma, we sought to identify novel or poorly characterized genes using the PCAWG dataset. We analyzed the RNA sequencing data from the TCGA endometrial cancer dataset, focusing on the copy-number high group. Genes that are highly expressed in the copy-number high endometrial cancer were identified by comparing the gene expression profiles between the copy-number high endometrial cancer dataset to genes expressed in normal endometrium obtained from the PCAWG project. Survival outcomes for genes of interest were evaluated using Kaplan-Meier Plotter, containing survival data extracted from the TCGA endometrial cancer dataset. <b>Results:</b> RNA transcripts that were significantly upregulated in copy-number high endometrial cancer were identified. Three of the most significantly upregulated transcripts were claudin-6 (<i>CLDN6</i>), cancer-testis antigen <i>MAGEA9B</i>, and long non-coding RNA <i>LINC01833</i>. Kaplan-Meier analysis of overall survival showed that high <i>CLDN6</i> expression was associated with worse overall survival when compared to low <i>CLDN6</i> expression (HR: 2.04 in White patients, p=0.0037; HR: 7.35 in Black patients, p=0.0002). High expression of <i>MAGEA9B</i> was also associated with worse overall survival than low <i>MAGEA9B</i> expression (HR: 1.78 in White patients, p=0.022; HR: 5.69 in Black patients, p=0.000033). In contrast, high expression of long non-coding RNA <i>LINC02159</i> was not associated with significant alteration in overall survival (HR: 1.28 in White patients, p=0.34, HR: 0.52 in Black patients, p=0.17). <b>Conclusions:</b> Integrated genomic analysis of the TCGA endometrial cancer dataset led to the identification of several novels, previously uncharacterized RNA transcripts that are associated with poor prognosis in copy-number high endometrial cancer. Further characterization of these transcripts in uterine serous carcinoma will improve our understanding of the biology of this disease and lead to novel therapeutic options.