Integrated proteogenomic characterization of urothelial carcinoma of the bladder

Background Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC patient cohort is lacking. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 116 Chinese UC patients, comprising 45 non-muscle-invasive bladder cancer patients (NMIBCs) and 71 muscle-invasive bladder cancer patients (MIBCs). Result Proteogenomic integration analysis indicated that SND1 and CDK5 amplifications on chromosome 7q were associated with the activation of STAT3, which was relevant to tumor proliferation. Chromosome 5p gain in NMIBC patients was a high-risk factor, through modulating actin cytoskeleton implicating in tumor cells invasion. Phosphoproteomic analysis of tumors and morphologically normal human urothelium produced UC-associated activated kinases, including CDK1 and PRKDC. Proteomic analysis identified three groups, U-I, U-II, and U-III, reflecting distinct clinical prognosis and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested the amplification of TRAF2 related to the increased expression of PD-L1. Additionally, increased GARS, related to subtype U-II, was validated to promote pentose phosphate pathway by inhibiting activities of PGK1 and PKM2. Conclusions This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in urothelial carcinoma of the bladder.

Automated summary

This study provides an integrated multi-omics analysis of Chinese UC patients, revealing the association between SND1 and CDK5 amplifications and the activation of STAT3 in tumor proliferation. It also identifies chromosome 5p gain as a high-risk factor in NMIBC patients through actin cytoskeleton modulation. Phosphoproteomic analysis identifies UC-associated activated kinases, and proteomic analysis groups UC patients into distinct prognostic and molecular signature categories. Immune subtypes of UC tumors demonstrate a complex immune landscape with the amplification of TRAF2 related to increased PD-L1 expression. Lastly, GARS is validated to promote the pentose phosphate pathway by inhibiting activities of PGK1 and PKM2 in U-II subtype.