Comparative Tumor Microenvironment Analysis of Primary and Recurrent Ovarian Granulosa Cell Tumors

Abstract

Adult-type granulosa cell tumors (aGCT) are rare ovarian sex cord tumors with few effective treatments for recurrent disease. The objective of this study was to characterize the tumor microenvironment (TME) of primary and recurrent aGCTs and to identify correlates of disease recurrence. Total RNA sequencing (RNA-seq) was performed on 24 pathologically confirmed, cryopreserved aGCT samples, including 8 primary and 16 recurrent tumors. After read alignment and quality-control filtering, DESeq2 was used to identify differentially expressed genes (DEG) between primary and recurrent tumors. Functional enrichment pathway analysis and gene set enrichment analysis was performed using “clusterProfiler” and “GSVA” R packages. TME composition was investigated through the analysis and integration of multiple published RNA-seq deconvolution algorithms. TME analysis results were externally validated using data from independent previously published RNA-seq datasets. A total of 31 DEGs were identified between primary and recurrent aGCTs. These included genes with known function in hormone signaling such as LHCGR and INSL3 (more abundant in primary tumors) and CYP19A1 (more abundant in recurrent tumors). Gene set enrichment analysis revealed that primarily immune-related and hormone-regulated gene sets expression was increased in recurrent tumors. Integrative TME analysis demonstrated statistically significant depletion of cancer-associated fibroblasts in recurrent tumors. This finding was confirmed in multiple independent datasets. Implications: Recurrent aGCTs exhibit alterations in hormone pathway gene expression as well as decreased infiltration of cancer-associated fibroblasts, suggesting dual roles for hormonal signaling and TME remodeling underpinning disease relapse.

Biophysical and biochemical aspects of immune cell–tumor microenvironment interactions

“…Recently, this technique has been used to explore differences within ovarian, prostate, and brain tumors. 27–29 As scRNA-seq research continues to evolve, clinicians can better identify specific cancer subtypes and adjust treatment appropriately.…”

DNA alterations in ovarian adult granulosa cell tumours: A scoping review protocol

“…Although trunctating KMT2D mutations, TERT promoter mutations and pathogenic TP53 variants have been reported in aGCT-cohorts, a pattern that describes prognostic markers is yet to be identified [17][18][19][20][27][28][29]. Interestingly, a recent study reported an increased expression of genes with hormone signalling functions in aGCT [30].…”

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“…Although trunctating KMT2D mutations, TERT promoter mutations and pathogenic TP53 variants have been reported in aGCT-cohorts, a pattern that describes prognostic markers is yet to be identified [17][18][19][20][27][28][29]. Interestingly, a recent study reported an increased expression of genes with hormone signalling functions in aGCT [30].…”