Altered TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR Predict Shorter Survival in Penile Squamous Cell Carcinoma
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
39694330
DOI
10.1016/j.modpat.2024.100689
PII: S0893-3952(24)00269-2
Knihovny.cz E-resources
- Keywords
- human papillomavirus, next-generation sequencing, penile, squamous cell carcinoma, tumor mutational burden,
- MeSH
- Ataxia Telangiectasia Mutated Proteins genetics MeSH
- Adult MeSH
- ErbB Receptors genetics MeSH
- Papillomavirus Infections MeSH
- Cyclin-Dependent Kinase Inhibitor p16 genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor * genetics analysis MeSH
- Tumor Suppressor Protein p53 genetics MeSH
- Penile Neoplasms * genetics mortality pathology virology MeSH
- Prognosis MeSH
- Telomere-Binding Proteins MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Shelterin Complex MeSH
- Carcinoma, Squamous Cell * genetics mortality pathology virology MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- ATM protein, human MeSH Browser
- Ataxia Telangiectasia Mutated Proteins MeSH
- CDKN2A protein, human MeSH Browser
- EGFR protein, human MeSH Browser
- ErbB Receptors MeSH
- Cyclin-Dependent Kinase Inhibitor p16 MeSH
- Biomarkers, Tumor * MeSH
- Tumor Suppressor Protein p53 MeSH
- POT1 protein, human MeSH Browser
- Telomere-Binding Proteins MeSH
- Shelterin Complex MeSH
- TP53 protein, human MeSH Browser
Penile squamous cell carcinoma (pSCC) represents an uncommon malignancy characterized by stagnant mortality, psychosexual distress, and a highly variable prognosis. Currently, the World Health Organization distinguishes between human papillomavirus (HPV)-related and HPV-independent pSCC. Recently, there has been an evolving line of research documenting the enrichment of HPV-independent pSCC with a high tumor mutational burden (TMB) and programmed death ligand-1 expression, as well as clusters of genes associated with HPV status. In this study, we conducted comprehensive next-generation sequencing DNA profiling of 146 pSCC samples using a panel consisting of 355 genes associated with tumors. This profiling was correlated with immunohistochemical markers and prognostic clinical data. A survival analysis of recurrent genomic events (found in ≥10 cases) was performed. TP53, CDKN2A, ATM, EPHA7, POT1, CHEK1, GRIN2A, and EGFR alterations were associated with significantly shortened overall survival in univariate and multivariate analysis. HPV positivity, diagnosed through both p16 immunohistochemistry and HPV DNA analysis, displayed no impact on survival but was associated with high-grade, lymphatic invasion, programmed death ligand-1 negativity/weak expression, and low TMB. FAT1, TP53, CDKN2A, CASP8, and HRAS were more often mutated in HPV-independent pSCC. In contrast, HPV-associated pSCCs were enriched by EPHA7, ATM, GRIN2A, and CHEK1 mutations. PIK3CA, FAT1, FBXW7, and KMT2D mutations were associated with high TMB. NOTCH1, TP53, CDKN2A, POT1, KMT2D, ATM, CHEK1, EPHA3, and EGFR alterations were related to adverse clinicopathologic signs, such as advanced stage, high tumor budding, and lymphovascular invasion. We detected 160 alterations with potential treatment implications, with 21.2% of samples showing alterations in the homologous recombination repair pathway. To the best of our knowledge, this study describes the largest cohort of pSCC with complex molecular pathologic, clinical, and prognostic analysis correlating with prognosis.
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