"Contextual" synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair

Abstract

Hypoxia exists in every solid tumor and is associated with poor prognosis because of both local and systemic therapeutic resistance. Recent studies have focused on the interaction between tumor cell genetics and the dynamic state of oxygenation and metabolism. Hypoxia generates aggressive tumor cell phenotypes in part owing to ongoing genetic instability and a "mutator" phenotype. The latter may be due to suppression of DNA mismatch repair (MMR), nucleotide excision repair (NER), and double-strand break (DSB) repair. We propose a theoretical model in which hypoxia-mediated defects in DNA repair can lead to "contextual loss of heterozygosity" and drive oncogenesis. Additionally, hypoxia-mediated repair defects can be specifically targeted by DNA damaging agents and/or "contextual synthetic lethality" to kill repair-deficient cells and preserve the therapeutic ratio. These proposed concepts support the interrogation of solid tumors to document repair defects in both oxic and hypoxic tumor subregions as a conduit to novel clinical trials within the context of personalized medicine.