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  • Processed Pseudogene Dysregulation in Testicular Germ Cell Tumors Reveals High-Contrast Molecular Candidates

  • Argam Margosian,1 Ali Kazemlou,2 Pouya Salehipour,3,*
    1. Medical Genetics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
    2. Medical Genetics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
    3. Medical Genetics Department, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran


  • Introduction: Testicular germ cell tumors (TGCTs) are among the most common malignancies affecting young men and encompass biologically heterogeneous tumor entities with distinctive molecular characteristics. While protein-coding genes and canonical regulatory pathways have been investigated extensively, the contribution of pseudogene transcription to TGCT remains comparatively underexplored. Processed pseudogenes were historically regarded as nonfunctional genomic remnants; however, accumulating evidence indicates that many are transcriptionally active and may participate in regulatory networks relevant to cancer biology. This study aimed to identify processed pseudogenes with large and consistent expression differences between TGCT and normal testicular tissue and to highlight candidates for further biological and translational investigation.
  • Methods: RNA-sequencing gene-expression data from 150 TGCT tumor samples from the TCGA-TGCT project and 450 normal testicular tissue samples from the GTEx project were analyzed. TCGA data were retrieved using the TCGAbiolinks package in R. Following preprocessing and sample level filtering, expression profiles were normalized and subjected to tumor–normal differential expression analysis. Genes annotated as processed pseudogenes according to their Ensembl gene biotype were subsequently selected. Differential expression was evaluated using log₂ fold change and multiple-testing-adjusted P-values. Candidate prioritization incorporated expression magnitude, statistical significance, and detection frequency. Detection frequency was calculated as the percentage of samples in each group with expression above the predefined detection threshold. Because processed pseudogenes may share sequence similarity with their parental genes or other genomic loci, potential multi-mapping and read-assignment specificity should be considered when interpreting their expression signals.
  • Results: Several processed pseudogenes exhibited exceptionally large differences between TGCT and normal testicular tissue. Four transcripts were strongly upregulated in tumors: NANOGP2 (log₂FC = 12.20, adjusted P = 3.29 × 10⁻¹⁴⁹), AC134879.2 (log₂FC = 12.08, adjusted P = 1.05 × 10⁻⁸⁴), AC008033.2 (log₂FC = 10.30, adjusted P = 1.16 × 10⁻¹²³), and BRWD1P1 (log₂FC = 10.29, adjusted P = 3.30 × 10⁻⁷⁶). NANOGP2 and AC008033.2 were detected in 82.0% and 85.3% of tumor samples, respectively, compared with 23.2% of normal samples. In contrast, RPL12P16 and EEF1DP2 showed pronounced tumor-associated loss of expression, with log₂FC values of −10.27 and −9.79, respectively. Both transcripts were detected in 100% of normal samples but in none of the tumor samples. The combination of large expression differences, highly significant adjusted P-values, and contrasting detection frequencies identifies these transcripts as high-contrast candidates associated with the TGCT transcriptomic state.
  • Conclusion: The analysis demonstrates substantial dysregulation of processed pseudogenes in TGCT and identifies six candidates with particularly strong tumor–normal expression contrasts. NANOGP2, AC134879.2, AC008033.2, and BRWD1P1 showed marked tumor-associated upregulation, whereas RPL12P16 and EEF1DP2 demonstrated complete loss of detectable expression in the tumor cohort. These findings expand the non-coding transcriptomic landscape of TGCT and provide candidates for further investigation. Given the independent TCGA–GTEx comparison and the potential for sequence-related read-assignment ambiguity among processed pseudogenes, independent cohort validation and assessment of mapping specificity will be important before biological or clinical interpretation.
  • Keywords: Testicular Germ Cell Tumor; Processed Pseudogenes; RNA Sequencing; Differential Gene Expression;

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