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

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 re...

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Autores principales: Luddy, Kimberly A., Teer, Jamie K., Freischel, Audrey, O’Farrelly, Cliona, Gatenby, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451599/
https://www.ncbi.nlm.nih.gov/pubmed/36092893
http://dx.doi.org/10.3389/fgene.2022.921447
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author Luddy, Kimberly A.
Teer, Jamie K.
Freischel, Audrey
O’Farrelly, Cliona
Gatenby, Robert
author_facet Luddy, Kimberly A.
Teer, Jamie K.
Freischel, Audrey
O’Farrelly, Cliona
Gatenby, Robert
author_sort Luddy, Kimberly A.
collection PubMed
description 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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spelling pubmed-94515992022-09-08 Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes Luddy, Kimberly A. Teer, Jamie K. Freischel, Audrey O’Farrelly, Cliona Gatenby, Robert Front Genet Genetics 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. Frontiers Media S.A. 2022-08-24 /pmc/articles/PMC9451599/ /pubmed/36092893 http://dx.doi.org/10.3389/fgene.2022.921447 Text en Copyright © 2022 Luddy, Teer, Freischel, O’Farrelly and Gatenby. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Luddy, Kimberly A.
Teer, Jamie K.
Freischel, Audrey
O’Farrelly, Cliona
Gatenby, Robert
Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title_full Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title_fullStr Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title_full_unstemmed Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title_short Evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
title_sort evolutionary selection identifies critical immune-relevant genes in lung cancer subtypes
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9451599/
https://www.ncbi.nlm.nih.gov/pubmed/36092893
http://dx.doi.org/10.3389/fgene.2022.921447
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