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Cross-cancer transcriptomic integration identifies a core immune-signaling network in hormone-driven malignancies
Prasanna Kumar Selvam1, Supraja Mohan1, Karthick Vasudevan1
1Manipal Academy of Higher Education (MAHE), Manipal, India; Institute of Bioinformatics, International Technology Park, Bangalore, India.
Abstract:
Hormone-dependent malignancies, including breast, ovarian, thyroid, and prostate cancers, are driven by dysregulated endocrine signaling but exhibit marked heterogeneity in molecular architecture and therapeutic response. Whether these cancers share conserved transcriptional programs that transcend tissue-of-origin remains incompletely understood. In this study, we applied a systematic, direction-aware transcriptomic framework to identify shared gene expression signatures across hormone-driven malignancies using RNA-sequencing data with matched non-malignant controls. Differential expression analysis was performed independently for each cancer type using DESeq2, identifying 15,648 significant differentially expressed genes (DEGs). Integration of DEGs across cancers using a presence-direction matrix revealed limited universal overlap, with only one gene shared across all four cancers. Leave-one-out sensitivity analysis demonstrated that prostate cancer exhibited reduced transcriptional concordance relative to other malignancies. Exclusion of prostate cancer resulted in the highest overlap and direction-consistent dysregulation, identifying 10,948 shared DEGs across breast, ovarian, and thyroid cancers, including 1043 genes with consistent regulatory direction. Restriction to genes common to all three retained cancers defined a core pan-hormone transcriptional signature comprising 270 genes. These genes were prioritized using a composite statistical score integrating mean absolute log2 fold change and Fisher-combined adjusted p-values across cancers. Functional enrichment analysis of the top 100 ranked genes using g:Profiler revealed significant enrichment of immune-related biological processes, cytokine signaling, membrane-associated signal transduction, and protein-protein interaction functions. Collectively, this study identifies a conserved immune-signaling-centric transcriptional program shared across breast, ovarian, and thyroid cancers.
Insights
This study found a shared immune-signaling transcriptional program in breast, ovarian, and thyroid cancers. Prostate cancer showed less overlap, suggesting distinct molecular drivers in hormone-driven malignancies.
Area of Science:
- Genomics and Molecular Biology
- Cancer Research
- Endocrinology
Background:
- Hormone-dependent cancers (breast, ovarian, thyroid, prostate) are driven by endocrine signaling but show molecular heterogeneity.
- Understanding shared transcriptional programs across these cancers is crucial for developing targeted therapies.
- Existing research has not fully elucidated conserved gene expression signatures in hormone-driven malignancies.
Purpose of the Study:
- To identify conserved gene expression signatures across hormone-driven cancers using a systematic transcriptomic framework.
- To investigate the degree of transcriptional overlap and directionality of gene dysregulation among breast, ovarian, thyroid, and prostate cancers.
- To define a core pan-hormone transcriptional signature and analyze its functional characteristics.
Main Methods:
- Applied a direction-aware transcriptomic framework to RNA-sequencing data from hormone-driven cancers and matched controls.
- Performed differential gene expression analysis using DESeq2 for each cancer type.
- Integrated differentially expressed genes (DEGs) across cancers using a presence-direction matrix and conducted leave-one-out sensitivity analysis.
Main Results:
- Identified 15,648 significant DEGs across the four cancer types, with limited universal overlap (only one gene shared across all four).
- Prostate cancer exhibited lower transcriptional concordance; excluding it revealed 10,948 shared DEGs across breast, ovarian, and thyroid cancers.
- A core pan-hormone signature of 270 genes was defined for breast, ovarian, and thyroid cancers, enriched for immune signaling and cytokine-related functions.
Conclusions:
- A conserved, immune-signaling-centric transcriptional program is shared among breast, ovarian, and thyroid cancers.
- Prostate cancer displays distinct transcriptional patterns compared to the other hormone-dependent malignancies studied.
- These findings highlight potential common therapeutic targets and underscore the importance of considering cancer-specific molecular profiles.
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