Low-fidelity compensatory backup alternative DNA repair pathways may unify current carcinogenesis theories.

Abstract

The somatic mutation carcinogenesis theory has dominated for decades. The alternative theory, tissue organization field theory, argues that the development of cancer is determined by the surrounding microenvironment. However, neither theory can explain all features of cancer. As cancers share the features of uncontrolled proliferation and genomic instability, they are likely to have the same pathogenesis. It has been found that various DNA repair pathways within a cell crosstalk with one another, forming a DNA repair network. When one DNA repair pathways is defective, the others may work as compensatory backups. The latter pathways are explored for synthetic lethal anticancer therapy. In this article, we extend the concept of compensatory alternative DNA repair to unify the theories. We propose that the microenvironmental stress can activate low-fidelity compensatory alternative DNA repair, causing mutations. If the mutation occurs to a DNA repair gene, this secondarily mutated gene can lead to even more mutated genes, including those related to other DNA repair pathways, eventually destabilizing the genome. Therefore, the low-fidelity compensatory alternative DNA repair may mediate microenvironment-dependent carcinogenesis. The proposal seems consistent with the view of evolution: the environmental stress causes mutations to adapt to the changing environment.