Inherent and toxicant-provoked reduction in DNA repair capacity: A key mechanism for personalized risk assessment, cancer prevention and intervention, and response to therapy

摘要

Genomic investigations reveal novel evidence which indicates that genetic predisposition and inherent drug response are key factors for development of cancer and for poor response to therapy. However, mechanisms for these outcomes and interactions with environmental factors have not been well-characterized. Therefore, cancer risk, prevention, intervention and prognosis determinations have still mainly been based on population, rather than on individualized, evaluations. The objective of this review was to demonstrate that a key mechanism which contributes to the determination is inherent and/or toxicant-provoked reduction in DNA repair capacity. In addition, functional and quantitative determination of DNA repair capacity on an individual basis would dramatically change the evaluation and management of health problems from a population to a personalized basis. In this review, justifications for the scenario were delineated. Topics to be presented include assays for detection of functional DNA repair deficiency, mechanisms for DNA repair defects, toxicant-perturbed DNA repair capacity, epigenetic mechanisms (methylation and miRNA expression) for alteration of DNA repair function, and bioinformatics approach to analyze large amount of genomic data. Information from these topics has recently been and will be used for better understanding of cancer causation and of response to therapeutic interventions. Consequently, innovative genomic- and mechanism-based evidence can be increasingly used to develop more precise cancer risk assessment, and target-specific and personalized medicine.