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Identification of important genes and drug repurposing based on clinical-centered analysis across human cancers.

ABSTRACT: Identification of the functional impact of mutated and altered genes in cancer is critical for implementing precision oncology and drug repurposing. In recent years, the emergence of multiomics data from large, well-characterized patient cohorts has provided us with an unprecedented opportunity to address this problem. In this study, we investigated survival-associated genes across 26 cancer types and found that these genes tended to be hub genes and had higher K-core values in biological networks. Moreover, the genes associated with adverse outcomes were mainly enriched in pathways related to genetic information processing and cellular processes, while the genes with favorable outcomes were enriched in metabolism and immune regulation pathways. We proposed using the number of survival-related neighbors to assess the impact of mutations. In addition, by integrating other databases including the Human Protein Atlas and the DrugBank database, we predicted novel targets and anticancer drugs using the drug repurposing strategy. Our results illustrated the significance of multidimensional analysis of clinical data in important gene identification and drug development.

SUBMITTER: Li Y

PROVIDER: S-EPMC8027787 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThere is increasing pre-clinical and clinical evidence that metformin, a commonly used diabetes medication, has a protective effect in cancer. The aim of this review is to discuss metformin's anti-cancer molecular mechanisms of action and to summarize the current literature demonstrating metformin's potential in gynecologic cancer prevention and treatment.MethodsA PubMed search was conducted combining the keywords "metformin" with "neoplasm", "uterine neoplasms", "ovarian neoplasms", and "uterine cervical neoplasms". Studies published in English between 1994 and 2014 were included.ResultsPre-clinical studies in endometrial, ovarian, and cervical cancer suggest that metformin inhibits the growth of cancer cells. The primary molecular mechanism mediating this effect appears to be the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of mammalian targets of rapamycin (mTOR). The pre-clinical findings are augmented by clinical studies indicating that metformin use is associated with a reduced risk of cancer and improved survival in diabetic women with ovarian and endometrial cancers. No clinical analyses have evaluated metformin use and cervical cancer. Overall, the data showing a favorable effect of metformin is strongest for endometrial and ovarian cancer and prospective clinical testing is ongoing in these two malignancies.ConclusionsNumerous clinical studies have reported an association between metformin use by diabetic patients and improved outcomes in gynecologic cancers. In addition, pre-clinical reports have identified plausible biological mechanisms to explain the molecular mechanism of action of metformin in cancer. However, the most important question remains unanswered: Will metformin be effective against cancer in patients without diabetes? Until this question is answered with prospective clinical testing, the role of metformin in the treatment or prevention of gynecologic malignancies remains theoretical and the clinical use of metformin as a cancer therapeutic is experimental.

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Identification of important genes and drug repurposing based on clinical-centered analysis across human cancers.

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