Predictability of Genetic Interactions from Functional Gene Modules

Young, Jonathan H.; Marcotte, Edward M.

doi:10.1101/049627

Cited by 2 publications

(3 citation statements)

References 27 publications

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“…Genomic alteration played an essential role in the occurrence and development of human cancers [36], [47]. Costain et al showed that the missense variants of Rac3 might cause a novel brain disorder [48].…”

Section: Discussionmentioning

confidence: 99%

Multiple Omics Analysis of the Rac3 Roles in Different Types of Human Cancer

Song

2022

IEEE Access

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Rac Family Small GTPase 3 (Rac3) is a member of the Rho family of small GTP-binding proteins which play critical roles in the occurrence, progression, and metastasis of various tumors. Nevertheless, previous studies have focused on a single type of human cancer, so that the roles of Rac3 in different cancer types have not been sufficiently clarified. With the progress of biological detection and bioinformatics technology, the emerging cancer genomics databases make it possible to perform a pancancer analysis. Therefore, for the first time, we performed multiple omics analysis to investigate the roles of Rac3 in differential expression, survival prognosis, mutative status, DNA methylation, functions, immune infiltration, and immunotherapy across 33 human cancer types. We found that Rac3 expression was abnormal in 17 cancer types and significantly different in both molecular and immune subtypes of 10 cancers (p<0.05). These Rac3 expression dysregulations in cancer tissues significantly affected their corresponding survival prognosis. Our results also indicated that genetic alterations of Rac3 occurred in 27 cancer types and were significantly associated with prognosis. Moreover, methylation of Rac3 was associated with dysfunctional T-cell phenotypes and affected the prognosis of the brain, melanoma, and breast tumors, and Rac3 Copy Number Alterations (CNA) might affect the infiltration levels of different immune cells in nine cancers. Rac3 and Rac3-related genes were enriched in the axon guidance, actin cytoskeleton regulation, and neurotrophin signaling pathway, and involved the regulation of cellular localization and actin cytoskeleton organization, and small GTPase mediated signal transduction. Then, we further explored the correlations between Rac3 expression and 25 immune cells and cancer-associated fibroblasts across 33 human cancers. Furthermore, we found that Rac3 achieved higher predictive power (AUC>0.5) than three standardized biomarkers of tumor immune responses and was associated with cytotoxic T-cell levels (CTLs) and the risk of immunotherapeutic responses in three cancer types. Collectively, our study contributes to a comprehensive and integrative understanding of the oncogenic roles of Rac3 across human cancers and offers a new clue for treatment strategies.INDEX TERMS Rac3, human cancer, multiple omics, cancer prognosis, immune infiltrating.

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Section: Discussionmentioning

confidence: 99%

Multiple Omics Analysis of the Rac3 Roles in Different Types of Human Cancer

Song

2022

IEEE Access

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“…These tumors are associated with pathogenic mutations in the BRCA genes. [82][83][84] Olaparib was approved in 2014 as maintenance therapy for recurrent, BRCA-mutated ovarian cancer, or for the treatment of BRCA-mutated advanced ovarian cancer (after 3 or more lines of chemotherapy). 85 In 2018, olaparib was finally approved by the FDA in first-line maintenance setting of BRCA-mutated advanced ovarian cancer.…”

Section: Parpismentioning

confidence: 99%

“…87,103 MPL stimulation by thrombopoietin results in the activation of AKT1 and ERK1/2 pathways leading to proliferation and apoptosis resistance of leukemia cells. 83 PARP1 is an important mediator of translocation common in AML (via the Alt-EJ pathway). 104 However, because data for MDS and AML treated with PARPi are still scarce, some concerns have arisen regarding delayed adverse events from PARPi.…”

Section: Parpismentioning

confidence: 99%

PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

et al. 2021

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Poly (ADP-ribose) polymerase-1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules, leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first PARP1 inhibitors (PARPi) were developed to target BRCA mutated cancer cells. Currently, PARPi are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib and the most recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of MDS/AML and we analyze the available data on the use of PARPi, highlighting their promising advances in clinical application.

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Predictability of Genetic Interactions from Functional Gene Modules

Cited by 2 publications

References 27 publications

Multiple Omics Analysis of the Rac3 Roles in Different Types of Human Cancer

Multiple Omics Analysis of the Rac3 Roles in Different Types of Human Cancer

PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome

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