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Multiplexed functional assessment of dominant genetic variants in CARD11

ABSTRACT: We describe the use of saturation genome editing to measure the effects of CARD11 variants on protein function, splicing and lymphoma cell survival. We find the results to predict the clinical effects of the variants.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152129 | GEO | 2020/07/01

REPOSITORIES: GEO

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Project description:The immune system plays a critical role in inflammation by initiating responses to infection or tissue damage. NF-κB pathway plays a key role in inflammation and innate immunity, as well as other cellular activities. Furthermore, dysregulation of this well-choreographed pathway has been observed in many diseases, including cancer. CARD11 is a key molecule in the BCL-10, MALT1 (CBM) complex which is involved in transducing the signal downstream of the NF-κB pathway. This study aims to understand how overexpression of CARD11 adversely affects the prognosis in colorectal cancer (CRC) as it progresses towards aggressive form of the disease and the role that CARD11 plays in modulating the immune response across the different stages of CRC. To identify some of the cellular pathways activated as a result of CARD11, whole tran-scriptomics analysis was carried comparing the transcriptomic profile of CARD11-overexpressed HCT-116 and HT-29 CRC cell lines with empty vector-transfected cell lines as well as comparing adenoma and carcinoma CRC patients with CARD11- and CARD11+ expression. The whole tran-scriptomics and bioinformatics analysis results strongly suggested that CARD11 appears to play a key role in CRC progression. Absolute Gene Set Enrichment Analysis (absGSEA) on HCT-116 transcriptomics data showed that CARD11 overexpression promotes cell growth, and tissue re-modeling as well as enhancing the cell’s immune response. Some of the underlying genes in-volved in such processes through co-expression with CARD11 include EP300, KDM5A, HIF1A, NFKBIZ, and DUSP1. Results for HT-29 showed that CARD11 overexpression induces chemotaxis and ECM organization pathways through co-expression of IL1RN, MDK, and SPP1 as well as var-ious chemokines including CXCL1, CXCL3 and CCL22 which were shown to contribute to the more invasive stage of CRC. For patients, the adenoma patients include genes related to tumour immune microenvironment such as IL6ST, genes related to collagen family as well as other genes related to transition to CRC such as GLI3 and PIEZO2. While carcinoma patients show dramatic increase in the expression of MAPK8IP2 in CARD11+ carcinoma patients in addition to other genes related to cancer processes including EMB, EPHB6, and CPEB4. Taken together, the results show that CARD11 overexpression contributes to the progression of CRC through modu-lation of various tumour immune microenvironment pathways and activation of cancer path-ways possibly via the dysregulation of NF-κB. To our knowledge, this is probably the first study that investigates the role of CARD11 in CRC and the genes and pathways associated with CARD11 overexpression may provide insights into the early diagnostic and possible therapeutic targets for CRC.

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Multiplexed functional assessment of dominant genetic variants in CARD11

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