Somatic Mutations Render Human Exome and Pathogen DNA more Similar
AbstractImmunotherapy has recently shown important clinical successes in a substantial number of oncology indications. Additionally, the tumor somatic mutation load has been shown to associate with response to these therapeutic agents, and specific mutational signatures are hypothesized to improve this association, including signatures related to pathogen insults. We sought to study in silico the validity of these observations and addressed three questions. First, we investigated whether somatic mutations typically involved in cancer may increase, in a statistically meaningful manner, the similarity between common pathogens and the human exome. Our study shows that specific common mutagenic processes like those resulting from exposure to ultraviolet light (in melanoma) or smoking (in lung cancer) induce, in the upper range of biologically plausible frequencies, peptides in the cancer exome that are statistically more similar to pathogen peptides than the normal exome. Second, we investigated whether this increased similarity is due to the specificities of the mutagenic process or uniformly random mutations at equal rate would trigger the same effect. For certain pathogens the increased similarity is more pronounced for specific mutagenic processes than for uniformly random mutations and for other pathogens the effects cannot be distinguished. Finally, we investigated whether specific mutational processes result in amino-acid changes with functional relevance that are more likely to be immunogenic. We showed that functional tolerance to mutagenic processes across species generally suggests more resilience to natural processes than to denovo mutagenesis. These results support the idea that recognition of pathogen sequences as well as differential functional tolerance to mutagenic processes may play an important role in the immune recognition process involved in tumor infiltration by lymphocytes.
