Dataset Information

Germline Variants Impact Somatic Events during Tumorigenesis.

ABSTRACT: Cancer is characterized by diverse genetic alterations in both germline and somatic genomes that disrupt normal biology and provide a selective advantage to cells during tumorigenesis. Germline and somatic genomes have been extensively studied independently, leading to numerous biological insights. Analyses integrating data from both genomes have identified genetic variants impacting somatic events in tumors, including hotspot driver mutations. Interactions among specific germline variants and somatic events influence cancer subtypes, treatment response, and clinical outcomes. Investigation of these complex interactions is increasing our understanding of aberrant pathways in tumors that may uncover novel therapeutic targets. Here, we review the literature describing the role of germline genetic variants in promoting the selection and generation of specific mutations during tumorigenesis.

SUBMITTER: Ramroop JR

PROVIDER: S-EPMC6571050 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Germline Variants Impact Somatic Events during Tumorigenesis.

Ramroop Johnny R JR Gerber Madelyn M MM Toland Amanda Ewart AE

Trends in genetics : TIG 20190522 7

Cancer is characterized by diverse genetic alterations in both germline and somatic genomes that disrupt normal biology and provide a selective advantage to cells during tumorigenesis. Germline and somatic genomes have been extensively studied independently, leading to numerous biological insights. Analyses integrating data from both genomes have identified genetic variants impacting somatic events in tumors, including hotspot driver mutations. Interactions among specific germline variants and s ...[more]

PMID: 31128889

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Project description:Advancements in next-generation sequencing (NGS) technologies are generating a vast amount of data. This exacerbates the current challenge of translating NGS data into actionable clinical interpretations. We have comprehensively combined germline and somatic nonsynonymous single-nucleotide variations (nsSNVs) that affect drug binding sites in order to investigate their prevalence. The integrated data thus generated in conjunction with exome or whole-genome sequencing can be used to identify patients who may not respond to a specific drug because of alterations in drug binding efficacy due to nsSNVs in the target protein's gene. To identify the nsSNVs that may affect drug binding, protein-drug complex structures were retrieved from Protein Data Bank (PDB) followed by identification of amino acids in the protein-drug binding sites using an occluded surface method. Then, the germline and somatic mutations were mapped to these amino acids to identify which of these alter protein-drug binding sites. Using this method we identified 12 993 amino acid-drug binding sites across 253 unique proteins bound to 235 unique drugs. The integration of amino acid-drug binding sites data with both germline and somatic nsSNVs data sets revealed 3133 nsSNVs affecting amino acid-drug binding sites. In addition, a comprehensive drug target discovery was conducted based on protein structure similarity and conservation of amino acid-drug binding sites. Using this method, 81 paralogs were identified that could serve as alternative drug targets. In addition, non-human mammalian proteins bound to drugs were used to identify 142 homologs in humans that can potentially bind to drugs. In the current protein-drug pairs that contain somatic mutations within their binding site, we identified 85 proteins with significant differential gene expression changes associated with specific cancer types. Information on protein-drug binding predicted drug target proteins and prevalence of both somatic and germline nsSNVs that disrupt these binding sites can provide valuable knowledge for personalized medicine treatment. A web portal is available where nsSNVs from individual patient can be checked by scanning against DrugVar to determine whether any of the SNVs affect the binding of any drug in the database.

Dataset Information

Germline Variants Impact Somatic Events during Tumorigenesis.

Publications

Germline Variants Impact Somatic Events during Tumorigenesis.

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