Yale scientists quantify preventable and age-related drivers across 24 cancer types

Researchers from Yale and Emmanuel College quantified the specific contributions of exogenous and endogenous mutational processes to tumor development across 24 cancer types, reporting their results in Molecular Biology and Evolution oup.comMolecular Biology and Evolutionoup.comOpen source ↗. The analysis focused on single-nucleotide variants within protein-coding regions identified via whole-exome sequencing to separate functional driver mutations from neutral passenger variations.

Most mutations detected in tumor sequencing have neutral or nearly neutral effects on cellular growth, meaning that mechanisms generating the majority of sequence alterations do not necessarily supply the primary tumorigenic drivers. To address this, the team coupled mutational signature profiles with natural selection metrics, calculating tumor-driving effects based on the ratio of observed substitutions relative to baseline neutral expectations.

Exogenous versus endogenous drivers

The evaluation showed that driver mutations in melanomas and lung cancers stem largely from preventable, exogenous exposures, specifically ultraviolet radiation and tobacco smoke. These environmental mutagens accounted for the highest proportion of single-nucleotide alterations actively selected for cell proliferation and lineage survival in those respective tissues.

In contrast, selected variants driving prostate adenocarcinomas and gliomas were predominantly traced to non-preventable endogenous biological processes associated with biological aging oup.comMolecular Biology and Evolutionoup.comOpen source ↗. These internal cellular events generate substitutions independently of external exposures, leading to distinct driver trajectories in central nervous system and prostate tissues.

Enzymatic and pathogen signatures

In head-and-neck, cervical, bladder, and breast malignancies, substantial shares of the selected oncogenic impact were attributable to pathogen exposure and the enzymatic activity of apolipoprotein B mRNA-editing enzymes (APOBEC). These enzymes induce recognizable sequence alterations during innate immune or antiviral responses.

The authors noted that the framework evaluated protein-coding point substitutions, leaving out structural variations such as large-scale copy number changes and chromosomal rearrangements. The approach establishes an analytical method to weight specific mutational signatures by their actual oncogenic selection across diverse anatomical sites.