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.

Proteogenomic insights into the biology and treatment of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis. Proteogenomic characterization and integrative proteomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. METHODS: We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 217 PDAC tumors with paired non-tumor adjacent tissues. In vivo functional experiments were performed to further illustrate the biological events related to PDAC tumorigenesis and progression. RESULTS: A comprehensive proteogenomic landscape revealed that TP53 mutations upregulated the CDK4-mediated cell proliferation process and led to poor prognosis in younger patients. Integrative multi-omics analysis illustrated the proteomic and phosphoproteomic alteration led by genomic alterations such as KRAS mutations and ADAM9 amplification of PDAC tumorigenesis. Proteogenomic analysis combined with in vivo experiments revealed that the higher amplification frequency of ADAM9 (8p11.22) could drive PDAC metastasis, though downregulating adhesion junction and upregulating WNT signaling pathway. Proteome-based stratification of PDAC revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Immune clustering defined a metabolic tumor subset that harbored FH amplicons led to better prognosis. Functional experiments revealed the role of FH in altering tumor glycolysis and in impacting PDAC tumor microenvironments. Experiments utilizing both in vivo and in vitro assay proved that loss of HOGA1 promoted the tumor growth via activating LARP7-CDK1 pathway. CONCLUSIONS: This proteogenomic dataset provided a valuable resource for researchers and clinicians seeking for better understanding and treatment of PDAC.

Molecular subtyping of hepatocellular carcinoma: A step toward precision medicine.

Hepatocellular carcinoma (HCC) is one of the most prevalent and fatal digestive tumors. Treatment for this disease has been constraint by heterogeneity of this group of tumors, which has greatly limited the progress in personalized therapy. Although existing studies have revealed the genetic and epigenetic blueprints that drive HCCs, many of the molecular mechanisms that lead to HCCs remain elusive. Recent advances in techniques for studying functional genomics, such as genome sequencing and transcriptomic analyses, have led to the discovery of molecular mechanisms that participate in the initiation and evolution of HCC. Integrative multi-omics analyses have identified several molecular subtypes of HCC associated with specific molecular characteristics and clinical outcomes. Deciphering similar molecular features among highly heterogeneous HCC patients is a prerequisite to implementation of personalized therapeutics. This review summarizes the current research progresses in precision therapy on the backbone of molecular subtypes of HCC.