title: Are GATA1 mutations occurring at random in Down syndrome transient leukemia?
abstract: The somatic mutation theory of cancer proposes that cancer begins with a somatic mutation occurring at random in a single cell that then passes the mutation to its progeny, generating a clone of premalignant cells. This clone leads to a full malignant tumor through additional mutations and selection processes. Strikingly, the best-documented human model of early oncogenesis, i.e., transient myeloproliferative disorder followed by acute megakaryoblastic leukemia (AMKL) in infants with Down syndrome (DS, or trisomy 21), exhibits important discrepancies with the SMT. Somatic mutations in megakaryocytic precursors occur at least 100,000 times more frequently in the GATA1 gene in fetuses with DS compared to the general population. Further, mutations are limited to GATA1 only; the general mutation rate does not significantly differ between individuals with DS and euploid individuals. Importantly, the mutations are also lineage-specific, occurring only in the megakaryocytic lineage, and proliferative anomalies of the megakaryocytic lineage are observed before the occurrence of GATA1 mutations. Thus, GATA1 mutations in fetuses with DS cannot be random events occurring in normal cells. Here, transcription-associated mutagenesis is proposed as the mechanism by which the earliest mutations of AMKL occur in DS. Transcription-associated mutagenesis is observed in non-dividing cells when a gene is over-expressed. The over-expression of GATA1 in the megakaryocytic lineage in DS fetal liver cells is proposed to be the cause of targeted GATA1 somatic mutations. As transcription-associated mutagenesis is a universal process, this mechanism may also apply to early oncogenesis in other situations, including after birth and following exposure to a carcinogenic agent. Thus, this hypothesis represents a new avenue for understanding and exploring oncogenesis in the context of DS and in other disease states.
authors.affiliation: Team Biostatistics Epidemiology Public Health, EA 2415, Oncodefi Project, University Institute for Clinical Research, Montpellier, France. Electronic address: danielsatge@orange.fr.
authors.forename: Daniel
authors.initials: D
authors.lastname: Satgé
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004314:Down Syndrome / Q000235:genetics*; D050982:GATA1 Transcription Factor / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007947:Leukemia, Megakaryoblastic, Acute / Q000235:genetics*; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics / Q000502:physiology; D059645:Mutation Rate; D009196:Myeloproliferative Disorders / Q000235:genetics*
chemical_list: D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human