Molecular Fingerprints in Adult and Pediatric Inflammatory Myofibroblastic Tumors of the Urinary Bladder

Document Type

Conference Proceeding

Publication Date

3-1-2024

Publication Title

Lab Invest

Abstract

Background: Inflammatory myofibroblastic tumor (IMT) is a rare spindle cell proliferation characterized by recurrent 2p22–23 alterations in the anaplastic lymphoma kinase (ALK). The debated neoplastic or pseudosarcomatous nature and the lack of the characteristic fusion in some cases make this tumor’s diagnosis challenging due to significant morphologic overlap with reactive or malignant mimickers. It affects both pediatric and adult population with a broad spectrum of age. Bladder is the most common site in the genitourinary system. This study aims to decipher the differential molecular alterations of bladder IMT in pediatric and adult patients. Design: Two pediatric and 5 adult patients diagnosed with IMT were investigated for molecular alterations using Illumina NovaSeq6000 (S4) PE150 RNA sequencing. Padj < 0.05 and fold changes ≥4 (both directions) were used as the threshold for detection of differentially expressed genes (DEGs) between adult and pediatric IMT. The core pathway analysis in the Ingenuity Pathway Analysis (IPA) package was used to identify the differential pathways (p < 0.05) based on the up- and down-regulated DEGs. Results: The clinicopathological features of the patients’ cohort are summarized in Table 1. Overall, 761 upregulated and 2,522 downregulated significant DEGs were identified respectively in adult compared to pediatric IMT. Among downregulated DEGs are immunoregulatory (CXCL15, IL15, CXCL2, IL23R) and DEAD box proteins (DDX1, DDX3, DX21, DDX56, DDX59). Several tumor growth-promoting genes including TGFB3, SMAD3, BRF1, MAPK7, and TCF20 were upregulated in adult IMTs (Figure 1). Pathway analysis of upregulated DEGs (P < 0.05) identified TGF-β and mTOR signaling, whereas the analysis of downregulated DEGs included ERK/MAPK, IL-3, IL10, and IL-15 signaling (P < 0.05) (Figure 2A-B). Importantly, expression levels of the main functional components of altered pathways, such as SMAD3 for TGF-β signaling, MAPK7 for ERK/MAPK signaling, were significantly upregulated with 43- and 81-fold change and IL15 was downregulated with 22-fold change in adult patients compared to those in pediatric patients, respectively. Conclusions: These exploratory findings suggest a differential role of multiple pathways in the pathogenesis of IMT in adult and pediatric IMTs, which may represent potential therapeutic targets. Larger studies are needed to support these preliminary data.

Volume

104

Issue

3

First Page

S1043

Last Page

S1045

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