Abstract C039: Cancer labeling should be retained for prostate cancer with a Gleason score of 3+3=6 - based on genomic, transcriptomic, and proteomic aspects

Abstract

Abstract Purpose: The decision to remove the cancer label for prostate cancer with a Gleason score (GS) of 3+3 relies on pathology and clinical manifestations. However, evidence at the molecular level, especially for comparing the Excluding 3 group (GS4+4, GS4+5, GS5+4 and GS5+5) and the Gleason Grade Group 1 (GG1) (GS3+3), is lacking. To address this gap, we aimed to explore the differences between these two groups at the genomic, transcriptomic, and proteomic levels. Methods: We compared the GG1 group (n=82) and Excluding 3 group (n=148) using data from the TCGA in terms of genomic alterations, including gene mutations, chromosomal structure variants, and copy number variants. Pathways were revealed by using GSEA enrichment analysis at the transcriptome level. We also conducted a quantitative whole protein analysis of prostate cancer and paraneoplastic tissues in 6 pairs of GG1 and 11 pairs of Excluding 3 groups to compare the differences at the protein level and explored the enriched pathways between them by GSEA enrichment analysis. Finally, we validated the accuracy of DIA quantification by performing immunohistochemical experiments on radical resection pathology specimens from 29 patients diagnosed with GG1 and 29 patients diagnosed with Excluding 3 group. Results: At the genomic level, we found that the mutation frequencies of GG1 and Excluding 3 group were comparable. But, the mutation frequencies of TP53, FOXA1 and PTEN were significantly higher in the Excluding 3 group than in the GG1 group , while the TMPRSS2-ERG fusion was not significantly different between the two groups. And the incidence of the p53 signaling pathway, WNT pathway, PI3K pathway, and DNA damage was significantly higher in the Excluding 3 group than in the GG1 group. For the transcriptomic level, GSEA enrichment analysis revealed that both groups were enriched for multiple tumor-related pathways. At the proteome level, with protein quantitative testing by mass spectrometry, we identified that androgen-response pathway was inhibited in the GG1 group, while DNA repair and PPAR signaling pathway was activated in the Excluding 3 group. Six differential proteins were identified which had important roles in cancer development. And immunohistochemical experiments confirmed the accuracy of quantification analysis for 3 representative proteins (DDX21, NOLC1, and TIMP1). Conclusion: The GG1 and Excluding 3 groups showed similar oncogene mutation frequencies and chromosomal structural variations. However, shared and distinct pathway alterations were observed in genomic and transcriptomic analyses, indicating common driving factors and differential influences of biological factors. Proteomic analysis identified differentially expressed proteins and enriched cancer-related pathways associated with tumor characteristics. These findings support the malignancy features of GG1 prostate cancer. Citation Format: Sijie Wen, Yinzhao Wang, Lin Qi, Hongling Yin, Xiaomei Gao, Minfeng Chen, Yi Cai. Cancer labeling should be retained for prostate cancer with a Gleason score of 3+3=6 - based on genomic, transcriptomic, and proteomic aspects [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C039.