Prostate cancer is the second most diagnosed cancer in men worldwide and a significant cause of cancer-related death. Proteogenomic analysis offers insights into how genomic mutations influence protein expression and can identify novel biomarkers. This study aimed to investigate the impact of missense mutations on protein abundance in prostate cancer versus healthy tissues using SILAC-based quantitative proteomics.
Methods
Mass spectrometry data from prostate tumors and adjacent healthy tissues were analyzed using stable isotope labeling. Peptides were classified based on their abundance into RefSeq and Variant Abundant groups. Missense mutations were mapped via RefSeq and dbPepVar databases. Protein intensity metrics were compared, and Spearman's correlation was used to evaluate the relationship between mutation presence and protein abundance.
Results
Functional enrichment revealed that RefSeq Abundant proteins are involved in normal metabolic and structural functions, while Variant Abundant proteins are enriched in tumor-related pathways such as immune evasion and apoptosis suppression. A significant negative correlation was found between protein intensity difference and ratio (p < 0.05), indicating that missense mutations contribute to altered protein expression. Mutation hotspot analysis identified recurrent alterations in genes such as PPIF and ACTB. PROVEAN was used to evaluate the functional impact of variants, identifying several as deleterious to protein stability and function.
Conclusions
Missense mutations influence protein abundance in prostate cancer. Using a SILAC-based quantitative proteomics approach, we identified significant proteomic differences between healthy and tumor tissues, demonstrating that missense mutations correlate with changes in protein expression. Specifically, RefSeq Abundant proteins were linked to essential metabolic and structural processes, while Variant Abundant proteins were associated with pathways involved in apoptosis inhibition, immune modulation, and metabolic reprogramming.
Spearman's correlation analysis revealed a significant negative correlation (p < 0.05) between protein intensity difference and protein intensity ratio, indicating that missense mutations contribute to alterations in protein abundance. Additionally, Oncodrive analysis identified ACTB and PPIF as mutation hotspots. ACTB mutations may affect cell adhesion and metastasis, while PPIF variants are linked to mitophagy regulation and tumor survival. PROVEAN classification further confirmed that specific mutations in PGK1, HSPA9, and MDH2 have deleterious effects on protein stability and function.
Unlike sequencing-based studies, which infer the effects of mutations, our proteogenomic approach directly validates their impact on protein expression, reinforcing their biological and clinical relevance. This methodology enabled the identification of novel mutations in PNP, CSRP1, and GEMIN6, suggesting potential roles in immune modulation, cytoskeletal organization, and metabolic adaptation. Furthermore, our findings highlight possible interactions between neutrophil-associated proteins and tumor immune evasion, warranting further investigation into their therapeutic potential.
Despite the strengths of this study, including the integration of proteomic and genomic data, some limitations must be considered. Dependence on existing databases may introduce biases, and further experimental validation is required to confirm the functional impact of the identified mutations. Future research should focus on in vitro and in vivo functional assays to establish mechanistic links between missense mutations and tumor progression, as well as their potential applications in targeted therapy and precision oncology.
In summary, this study advances the understanding of prostate cancer biology by demonstrating the role of missense mutations in shaping the tumor proteome. These findings contribute to the identification of potential biomarkers and therapeutic targets, supporting the development of more precise diagnostic and treatment strategies.
Full text
https://www.xiahepublishing.com/2996-3427/OnA-2024-00032
The study was recently published in the Oncology Advances .
Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.
