Variable Mutation Expression in Human Cancers: A "Hide-and-Seek" Mechanism Linked to Differential MHC-I Presentation Dynamics. Mol Cancer Ther 2022 Jul 05;21(7):1219-1226
Date
05/12/2022Pubmed ID
35545005DOI
10.1158/1535-7163.MCT-21-0831Scopus ID
2-s2.0-85134083568 (requires institutional sign-in at Scopus site)Abstract
Not all genomic mutations are expressed at the transcript/protein level, which may explain variation in cancer development, prognosis, and treatment response/resistance. In this study, our aim was to describe the prevalence of somatic mutation loss of expression ('variant silencing') in a large collection of human samples, and the potential impact of such variant silencing on tumor immunogenicity. Whole-exome mutation description and tumor-normal paired mRNA expression data originating from 636 unique patients diagnosed with 21 distinct tumor types (all solid tumors) were retrieved from The Cancer Genome Atlas (TCGA). Antigenicity and immunogenicity of neopeptides originating from mutated proteins within a same tumor sample were predicted using the tools available from the Immune Epitope Database (IEDB). A total of 65,072 missense mutations were studied. We demonstrated that 9.06% (N = 10,604 silenced/117,505 total variants) somatic variants were silenced in human tumors. Transciptomic silencing is significantly associated with proteins presenting better peptide processing, MHC-I binding, and T-cell recognition; and is more likely observed in lymphocyte-depleted tumors. Silencing may participate in tumor resistance by clonal selection and immune evasion. In the era of precision medicine, we suggest that therapeutic choices should be informed by both the presence of a genomic mutation and its actual transcript expression.
Author List
Boichard A, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antigen PresentationHistocompatibility Antigens Class I
Humans
Mutation
Mutation, Missense
Neoplasms
Prognosis