Somatic Variations in Mutational Signatures in Retrospect to Ovarian Cancer
Open AccessCancer is a mutational process and mutations drive evolution of cancer cells and avoidance of therapy. Understanding the mutational mechanisms is important. Mutational signatures are characteristic patterns of somatic mutations in cancer genomes, reflecting the underlying mutational processes.Identifying the mutagenic processes underlying the observed mutational signatures is an important step toward understanding tumor genesis and cancer evolution. Moreover, the understanding of mutational processes acting on a patient's genome might also help to develop personalized therapies. Somatic mutations in cancer genomes are caused by multiple mutational processes, of both exogenous and endogenous origin, each of which generates a characteristic mutational signature. The previous analysis by several groups (e.g. Ludmil Alexandrov et al, “The repertoire of mutational signatures in human cancer” Nature volume 578, pages94–101 (2020)), has identified many of such mutational signatures, and a catalogue of the reference signatures is available at https://cancer.sanger.ac.uk/cosmic/signatures . By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, the associations of signatures to exogenous (UV light) or endogenous (APOBEC enzymes, reactive oxygen species) exposures, as well as to defective DNA-maintenance processes, have been established. However, many signatures are of unknown cause. We hypothesized that many of unknown signatures are caused by the cellular enzymatic systems dysregulated in cancer and propose to perform a systematic search for such enzymes by correlating the presence of a specific signature and the levels of expression for different cellular enzymes. Specifically, we are interested to evaluate the influence of LINE-1 retrotransposon activation on the appearance of mutational signatures, as the endonuclease/revertase of LINE-1 is known to induce DNA nicks as a part of retrotransposition process. As a result of this analysis, we were able to discover a greater understanding of the Mutational Signatures involved in Ovarian Cancer. By working on this analysis, we are hoping to understand what specific mutational signatures are associated with our data as well as more present. Our hope is to gain a better understanding of the mutational patterns that occur so that insight can help the medical world in creating more treatment options based on these discoveries.
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Fenstermaker_gwu_0075M_16438.pdf | 2024-01-11 | Open Access |
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