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Abstract 5005: PSMB9/LMP2 as a controversial diagnostic biomarker for uterine leiomyosarcoma


 Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the cells of the myometrium. Diagnosis is based on histopathological features. Developing effective therapies against uLMS is a challenge due its resistance to conventional radiation and chemotherapy. In vivo and in vitro models for uLMS are urgently needed and it has been proposed that knockout mice for the gene PSMB9 (MIM:177045), also known by LMP2, could be a good model to study uLMS. Previous studies using mice homozygous deficiency for PSMB9 presented abnormalities in the biological functions of the immunoproteasome and spontaneously developed uLMS thus suggesting this gene as a tumor suppressor gene. Furthermore, expression of PSMB9 was suggested to be a specific biomarker for the diagnosis of uLMS. The goal of this study was to evaluate the role of PSMB9 in uLMS using in silico analysis of transcriptomics data from a patient cohort, combined with publicly available datasets. Molecular data were integrated and used for a meta-analysis of RNA-seq in order to find Differentially Expressed Genes (DEGs). A total of 68, 66 and 67 samples from normal myometrium (MM), uterine leiomyoma (LM) and uLMS, respectively, were analyzed. A quality control followed by adapter removal and alignment step was assessed using FastQC, Trim-galore and HISAT2 software respectively and counting reads was performed using htseq-count. Expression values were calculated as Transcripts Per Million (TPM) in order to remove libraries dependencies. Differential expression analysis was done using DESeq2 and edgeR and genes were classified as DEG when that had adjusted p-value < 0.01 and |log2FC| ≥ 2 in both packages. Gene Set Enrichment Analysis was performed using fgsea package with 100,000 permutations and MSigDB collections (KEGG and Reactome) as input parameters. Our results showed an over-expression of PMSB9 in uLMS samples and immune-related pathways were significantly enriched. Moreover, the overall survival analysis for the outcome of uLMS patients based on PSMB9 expression in TCGA showed no significant changes, further questioning the importance of PSMB9 in uLMS malignancy. Finally, based on phylogenetic analysis we showed that PSMB9 conservation between Mus musculus and Homo sapiens is not closely related. This divergence suggests that the biological role of PSMB9 may differ between M. musculus and H. sapiens. Human uLMS exhibits an over-expression in PSMB9 and these findings suggest PSMB9-deficient mice are not an appropriate diagnostic-biomarker for uLMS.
 Citation Format: Raul Maia, Georgia Kokaraki, Jorge E. Souza, Joseph W. Carlson, Tirzah B. Petta. PSMB9/LMP2 as a controversial diagnostic biomarker for uterine leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5005.