Identification of novel loss of heterozygosity collateral lethality genes for potential applications in cancer
Sammanfattning: Over the course of this project, I demonstrate the utility of a 4-phase analysis pipeline in the context of cancer therapy and the associated search for antineoplastic drug candidates. I showcase a repeatable means for generating lists of potential targets which may be used in conjunction with methods like small molecule screening as part of a search for broadly effective antineoplastic agents. By using publicly available variant call format (VCF) data sourced from the 1000 genomes project, global human population-wide data for non-sex chromosomes was filtered and transformed in a 4-phase process to obtain high population frequency, heterozygotic, nonsynonymous single nucleotide variants (nsSNVs) residing in functional domains of proteins. Through manual filtration combined with software-assisted annotation, I obtained a ranked list of 50 top scoring annotated variants across the human autosome, all residing in known protein domains. Additionally, a single top variant was selected for proof-of-concept structure prediction and visualization. When the methodology outlined herein is coupled to additional loss-of-heterozygosity (LOH) prevalence data across cancer genomes, it may be used to identify candidate variants which collectively represent potential loss-of-heterozygosity based collateral lethalities (CL) in the underlying cancer. Furthermore, under the assumption that subsequent methods like small molecule screening succeed in finding molecule(s) targeting a structural aspect of one of these variants, any subsequently developed therapeutic approaches may possess broader therapeutic utility dependent upon the strictness of the initial heterozygotic filtering threshold applied at the onset of the project pipeline. When combined with additional cancer data, the recreation of such gene lists at other degrees of heterozygotic thresholding can allow for the creation of lists of autosomal loss-of-heterozygosity gene candidates, representing potential collateral lethality targets with varied degrees of utility dependent upon the strictness of the initial filtration threshold.
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