Journal Article Ppublish
PubMed: 41562193 DOI: 10.1002/gcc.70106
Endogenous Processes Underlying Clock-Like Mutational Signatures.
Genes Chromosomes Cancer 65(1):e70106
Authors: Teresa Druck, Rami I Aqeilan, C Marcelo Aldaz, Nicola Zanesi, Kay Huebner
Affiliations
- Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
- Lautenberg Center for Immunology & Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
- Molecular Basis of Cancer (MoBaC) Group, Cyprus Cancer Research Institute (CCRI), Nicosia, Cyprus.
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Abstract
Wellcome Trust scientists have shown that "mutational signatures" in specific nucleotide contexts accumulate in genomes of mammalian tissues, providing clues to underlying causes of specific signatures. Analysis of cancer genomes has identified more than 50 single-base substitution (SBS) signatures, with SBS1, SBS5, and SBS40 linked to aging and present in normal tissues. SBS1 results from cytosine demethylation, whereas SBS5 and SBS40 arise from unknown endogenous mechanisms. We hypothesized that loss of fragile-site genes drives these two signatures. FHIT, located at FRA3B, is frequently deleted in cancers, and Fhit-deficient mouse tissues exhibit a mutation profile resembling human SBS5. Data mining of cancer genome sequences showed that FHIT/Fra3B was the gene loss most significantly correlated with human SBS5 mutations, likely representing the endogenous molecular process determining SBS5 mutations in soma, germ cells, and cancers, and inversely associated with lifespan in mammals. Exome sequences of Fhit knockout tissues revealed ~1000 SBS1 and ~4000 SBS5 mutations per sample, compared to markedly fewer in wild-type controls. Using SigProfilerAssignment, similar analyses performed with Fhit ko samples where Wwox is also frequently lost identified SBS40c. These findings implicate fragile-site gene inactivation as a major source of clock-like mutational signatures, contributing to lifelong mutation accumulation and potentially influencing aging, evolution, and speciation.
MeSH
Genes, Aging, Neoplasms, Genome, Chromosome Aberrations, Tissues, Mutation