-
Trends in Immunology Nov 2023Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified... (Review)
Review
Inborn errors of immunity (IEIs) comprise a variety of immune conditions leading to infections, autoimmunity, allergy, and cancer. Some IEIs have no identified mutation(s), while others with identical mutations can display heterogeneous presentations. These observations suggest the involvement of epigenetic mechanisms. Epigenetic alterations can arise from downstream activation of cellular pathways through both extracellular stimulation and genetic-associated changes, impacting epigenetic enzymes or their interactors. Therefore, we posit that epigenetic alterations and genetic defects do not exclude each other as a disease-causing etiology. In this opinion, encompassing both basic and clinical viewpoints, we focus on selected IEIs with mutations in transcription factors that interact with epigenetic enzymes. The intricate interplay between these factors offers insights into genetic and epigenetic mechanisms in IEIs.
Topics: Humans; Autoimmunity; Epigenesis, Genetic; Epigenomics; Hypersensitivity; Mutation
PubMed: 37813732
DOI: 10.1016/j.it.2023.09.005 -
Leukemia Feb 2024Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of...
Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP), frameshift InDel or nonsense mutations inducing translational stop (bZIP) or single base-pair missense alterations (bZIP), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP).
Topics: Adult; Humans; CCAAT-Enhancer-Binding Proteins; Frameshift Mutation; Leukemia, Myeloid, Acute; Mutation; Prognosis
PubMed: 38228680
DOI: 10.1038/s41375-024-02140-x -
Nature Communications Jul 2023A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly...
A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.
Topics: Humans; Mutation; Mutagenesis; Esophageal Neoplasms; Adenocarcinoma
PubMed: 37454136
DOI: 10.1038/s41467-023-39957-6 -
Pathology International Sep 2023Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a... (Review)
Review
Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy-resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy-resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non-CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non-CSCs. The plasticity of tumor phenotypes between CSCs and non-CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1-expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non-mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non-mutational epigenetic reprogramming in tumors are also discussed.
Topics: Humans; Pathologists; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Mutation
PubMed: 37638598
DOI: 10.1111/pin.13366 -
European Journal of Human Genetics :... Oct 2023Germline mutations in MBD4, which, like MUTYH and NTHL1, encodes a glycosylase of the DNA based excision repair system, cause an autosomal recessive syndrome...
Germline mutations in MBD4, which, like MUTYH and NTHL1, encodes a glycosylase of the DNA based excision repair system, cause an autosomal recessive syndrome characterised by increased risk of acute myeloid leukaemia, gastrointestinal polyposis, colorectal cancer (CRC) and, to a lesser extent, uveal melanoma and schwannomas. To better define the phenotypic spectrum and tumour molecular features associated with biallelic MBD4-associated cancer predisposition, and study if heterozygous variants are associated with gastrointestinal tumour predisposition, we evaluated germline MBD4 status in 728 patients with CRC, polyposis, and other suggestive phenotypes (TCGA and in-house cohorts). Eight CRC patients carried rare homozygous or heterozygous germline variants in MBD4. The information gathered on mode of inheritance, variant nature, functional effect of the variant, and tumour mutational characteristics suggested that none of the patients included in the study had an MBD4-associated hereditary syndrome and that the heterozygous variants identified were not associated with the disease.
Topics: Humans; Genetic Predisposition to Disease; Colorectal Neoplasms; Mutation; Phenotype; Germ-Line Mutation; Endodeoxyribonucleases
PubMed: 37402954
DOI: 10.1038/s41431-023-01418-5 -
Proceedings of the National Academy of... Aug 2023The tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent alterations are missense mutations...
The tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream analyses revealed that deletion of mutant activated the cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway but did not cause apoptosis implicating other mechanisms of tumor regression. Furthermore, we determined that only tumors with stable mutant p53 are dependent on mutant p53 for growth.
Topics: Animals; Humans; Mice; Genes, p53; Mutation; Mutation, Missense; Triple Negative Breast Neoplasms; Tumor Microenvironment; Tumor Suppressor Protein p53
PubMed: 37579145
DOI: 10.1073/pnas.2308807120 -
Cell Reports Aug 2023The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be...
The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome-sequenced tumors from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features, with signatures of related etiologies being similarly affected. Certain signatures exhibit periodic behaviors or cancer-type-specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via the COSMIC (Catalog of Somatic Mutations in Cancer) signatures database, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer.
Topics: Humans; Mutation; Neoplasms; Genomics; Base Sequence; Genome, Human
PubMed: 37540596
DOI: 10.1016/j.celrep.2023.112930 -
Bulletin Du Cancer Nov 2023During aging, the onset of mutations at low frequency in hematopoietic cells or clonal hematopoiesis of indeterminate significance favors the evolution towards... (Review)
Review
During aging, the onset of mutations at low frequency in hematopoietic cells or clonal hematopoiesis of indeterminate significance favors the evolution towards hemopathies such as myelodysplastic syndromes or acute leukemias, but also cardiovascular diseases and other pathologies. Acute or chronic inflammation related to age influences the clonal evolution and the immune response. Conversely, mutated hematopoietic cells create an inflammatory bone marrow environment facilitating their expansion. Various pathophysiological mechanisms depending on the type of mutation produce the diversity of phenotypes. Identifying factors affecting clonal selection is mandatory to improve patient care.
Topics: Humans; Hematopoiesis; Myelodysplastic Syndromes; Bone Marrow; Leukemia; Mutation
PubMed: 37423830
DOI: 10.1016/j.bulcan.2023.02.026 -
American Journal of Respiratory and... Dec 2023Constantly exposed to the external environment and mutagens such as tobacco smoke, human lungs have one of the highest somatic mutation rates among all human organs....
Constantly exposed to the external environment and mutagens such as tobacco smoke, human lungs have one of the highest somatic mutation rates among all human organs. However, the relationship of these mutations to lung disease and function is not known. To identify the prevalence and significance of clonal somatic mutations in chronic lung diseases. We analyzed the clonal somatic mutations from 1,251 samples of normal and diseased noncancerous lung tissue RNA sequencing with paired whole-genome sequencing from the Lung Tissue Research Consortium. We examined the associations of somatic mutations with lung function, disease status, and computationally deconvoluted cell types in two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD; 29%) and idiopathic pulmonary fibrosis (IPF; 13%). Clonal somatic mutational burden was associated with reduced lung function in both COPD and IPF. We identified an increased prevalence of clonal somatic mutations in individuals with IPF compared with normal control subjects and individuals with COPD independent of age and smoking status. IPF clonal somatic mutations were enriched in disease-related and airway epithelial-expressed genes such as in IPF. Patients who were risk variant carriers had increased odds of developing somatic mutations of that were explained by increased expression of . Our identification of an increased prevalence of clonal somatic mutation in diseased lung that correlates with airway epithelial gene expression and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Lung; Mutation; Respiratory Physiological Phenomena; Pulmonary Disease, Chronic Obstructive
PubMed: 37788444
DOI: 10.1164/rccm.202303-0395OC -
Proceedings of the National Academy of... Aug 2023RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions...
RNA viruses rapidly adapt to selective conditions due to the high intrinsic mutation rates of their RNA-dependent RNA polymerases (RdRps). Insertions and deletions (indels) in viral genomes are major contributors to both deleterious mutational load and evolutionary novelty, but remain understudied. To characterize the mechanistic details of their formation and evolutionary dynamics during infection, we developed a hybrid experimental-bioinformatic approach. This approach, called MultiMatch, extracts insertions and deletions from ultradeep sequencing experiments, including those occurring at extremely low frequencies, allowing us to map their genomic distribution and quantify the rates at which they occur. Mapping indel mutations in adapting poliovirus and dengue virus populations, we determine the rates of indel generation and identify mechanistic and functional constraints shaping indel diversity. Using poliovirus RdRp variants of distinct fidelity and genome recombination rates, we demonstrate tradeoffs between fidelity and Indel generation. Additionally, we show that maintaining translation frame and viral RNA structures constrain the Indel landscape and that, due to these significant fitness effects, Indels exert a significant deleterious load on adapting viral populations. Conversely, we uncover positively selected Indels that modulate RNA structure, generate protein variants, and produce defective interfering genomes in viral populations. Together, our analyses establish the kinetic and mechanistic tradeoffs between misincorporation, recombination, and Indel rates and reveal functional principles defining the central role of Indels in virus evolution, emergence, and the regulation of viral infection.
Topics: Evolution, Molecular; Genome; Mutation Rate; INDEL Mutation; RNA, Viral; RNA Viruses
PubMed: 37487061
DOI: 10.1073/pnas.2304667120