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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE220067 | GEO | 2022/12/07

REPOSITORIES: GEO

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

Project description:Inflammation has long been recognized to contribute to cancer development, particularly across the gastrointestinal tract. Patients with inflammatory bowel disease have an increased risk for bowel cancers, and it has been posited that a field of genetic changes may underlie this risk. Here, we define the clinical features, genomic landscape, and germline alterations in 174 patients with colitis-associated cancers and sequenced 29 synchronous or isolated dysplasia. TP53 alterations, an early and highly recurrent event in colitis-associated cancers, occur in half of dysplasia, largely as convergent evolution of independent events. Wnt pathway alterations are infrequent, and our data suggest transcriptional rewiring away from Wnt. Sequencing of multiple dysplasia/cancer lesions from mouse models and patients demonstrates rare shared alterations between lesions. These findings suggest neoplastic bowel lesions developing in a background of inflammation experience lineage plasticity away from Wnt activation early during tumorigenesis and largely occur as genetically independent events. Colitis-associated cancers (CACs) develop in patients with inflammatory bowel disease and have distinct genomic features compared to sporadic colorectal cancers. Here, the authors characterize the genomic alterations of CAC tumors and dysplasia, finding decreased Wnt signaling and a lack of shared early genetic steps.

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Z]

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_W]

2022-12-07 | GSE220063 | GEO

Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Q]

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

Project description:Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Q]

Project description:Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Q]

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Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_W]

Project description:Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_W]

| PRJNA908745 | ENA

Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Z]

Project description:Integrated clinical and genomic analysis identifies driver events and molecular evolution of colitis-associated cancers [Proj_07182_Z]

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Integrated in vivo multiomics analysis identifies p21-activated kinase signaling as a driver of colitis.

Project description:Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract that has limited treatment options. To gain insight into the pathogenesis of chronic colonic inflammation (colitis), we performed a multiomics analysis that integrated RNA microarray, total protein mass spectrometry (MS), and phosphoprotein MS measurements from a mouse model of the disease. Because we collected all three types of data from individual samples, we tracked information flow from RNA to protein to phosphoprotein and identified signaling molecules that were coordinately or discordantly regulated and pathways that had complex regulation in vivo. For example, the genes encoding acute-phase proteins were expressed in the liver, but the proteins were detected by MS in the colon during inflammation. We also ascertained the types of data that best described particular facets of chronic inflammation. Using gene set enrichment analysis and trans-omics coexpression network analysis, we found that each data set provided a distinct viewpoint on the molecular pathogenesis of colitis. Combining human transcriptomic data with the mouse multiomics data implicated increased p21-activated kinase (Pak) signaling as a driver of colitis. Chemical inhibition of Pak1 and Pak2 with FRAX597 suppressed active colitis in mice. These studies provide translational insights into the mechanisms contributing to colitis and identify Pak as a potential therapeutic target in IBD.

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Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer.

Project description:Pediatric liver cancers (PLC) comprise diverse diseases affecting infants, children, and adolescents. Despite overall good prognosis, PLCs display heterogeneous response to chemotherapy. Integrated genomic analysis of 126 pediatric liver tumors showed a continuum of driver mechanisms associated with patient age, including new targetable oncogenes. In 10% of patients with hepatoblastoma, all before three years old, we identified a mosaic premalignant clonal expansion of cells altered at the 11p15.5 locus. Analysis of spatial and longitudinal heterogeneity revealed an important plasticity between "hepatocytic," "liver progenitor," and "mesenchymal" molecular subgroups of hepatoblastoma. We showed that during chemotherapy, "liver progenitor" cells accumulated massive loads of cisplatin-induced mutations with a specific mutational signature, leading to the development of heavily mutated relapses and metastases. Drug screening in PLC cell lines identified promising targets for cisplatin-resistant progenitor cells, validated in mouse xenograft experiments. These data provide new insights into cisplatin resistance mechanisms in PLC and suggest alternative therapies. SIGNIFICANCE: PLCs are deadly when they resist chemotherapy, with limited alternative treatment options. Using a multiomics approach, we identified PLC driver genes and the cellular phenotype at the origin of cisplatin resistance. We validated new treatments targeting these molecular features in cell lines and xenografts.This article is highlighted in the In This Issue feature, p. 2355.

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