4.6 Article

Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes

Journal

FRONTIERS IN GENETICS
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2022.921447

Keywords

cancer evolution; cancer immunology; evolutionary triage; gene conservation; immune evasion

Funding

  1. NCI Comprehensive Cancer Center Grant [P30 CA076292]
  2. State of Florida
  3. [U54 CA143970]
  4. [R01 CA077575]
  5. [U01CA232382]

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In an evolving population, fitness determines proliferation and the dominant population usually has the most well adapted phenotype. Negative selection provides crucial information about genes involved in essential cellular processes. Similar to immunoediting, evolutionary triage eliminates mutations in tumor cells that increase susceptibility to immune response while mutations that shield them from immune attack increase proliferation. This new approach can be used to investigate evolutionary triage in immune-related genes and potentially lead to new treatment options.
In an evolving population, proliferation is dependent on fitness so that a numerically dominant population typically possesses the most well adapted phenotype. In contrast, the evolutionary losers typically disappear from the population so that their genetic record is lost. Historically, cancer research has focused on observed genetic mutations in the dominant tumor cell populations which presumably increase fitness. Negative selection, i.e., removal of deleterious mutations from a population, is not observable but can provide critical information regarding genes involved in essential cellular processes. Similar to immunoediting, evolutionary triage eliminates mutations in tumor cells that increase susceptibility to the host immune response while mutations that shield them from immune attack increase proliferation and are readily observable (e.g., B2M mutations). These dynamics permit an inverse problem analysis linking the fitness consequences of a mutation to its prevalence in a tumor cohort. This is evident in driver mutations but, equally important, can identify essential genes in which mutations are seen significantly less than expected by chance. Here we utilized this new approach to investigate evolutionary triage in immune-related genes from TCGA lung adenocarcinoma cohorts. Negative selection differs between the two cohorts and is observed in endoplasmic reticulum aminopeptidase genes, ERAP1 and ERAP2 genes, and DNAM-1/TIGIT ligands. Targeting genes or molecular pathways under positive or negative evolutionary selection may permit new treatment options and increase the efficacy of current immunotherapy.

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