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Nature Jan 2012Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The... (Review)
Review
Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.
Topics: Animals; Clonal Evolution; Clone Cells; Genomics; Humans; Mutation; Neoplasms; Neoplastic Stem Cells; Tumor Microenvironment
PubMed: 22258609
DOI: 10.1038/nature10762 -
Nature Reviews. Genetics Jan 2021Cancer represents an evolutionary process through which growing malignant populations genetically diversify, leading to tumour progression, relapse and resistance to... (Review)
Review
Cancer represents an evolutionary process through which growing malignant populations genetically diversify, leading to tumour progression, relapse and resistance to therapy. In addition to genetic diversity, the cell-to-cell variation that fuels evolutionary selection also manifests in cellular states, epigenetic profiles, spatial distributions and interactions with the microenvironment. Therefore, the study of cancer requires the integration of multiple heritable dimensions at the resolution of the single cell - the atomic unit of somatic evolution. In this Review, we discuss emerging analytic and experimental technologies for single-cell multi-omics that enable the capture and integration of multiple data modalities to inform the study of cancer evolution. These data show that cancer results from a complex interplay between genetic and non-genetic determinants of somatic evolution.
Topics: Clonal Evolution; Computational Biology; Epigenomics; Genetic Variation; Genomics; Humans; Mutation; Neoplasms; Single-Cell Analysis; Tumor Microenvironment
PubMed: 32807900
DOI: 10.1038/s41576-020-0265-5 -
Blood Oct 2020Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal... (Review)
Review
Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis with other nonhematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and nonmalignant diseases of aging.
Topics: Animals; Biomarkers; Cardiovascular Diseases; Clonal Evolution; Clonal Hematopoiesis; Disease Susceptibility; Genetic Association Studies; Genetic Predisposition to Disease; Hematopoiesis; Humans; Mutation; Organ Specificity; Phenotype; Terminology as Topic
PubMed: 32736379
DOI: 10.1182/blood.2019000989 -
Annual Review of Pathology Jan 2020Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have... (Review)
Review
Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.
Topics: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cells, Cultured; Clonal Evolution; Hematopoiesis; Humans; Incidence; Mutation; Risk Factors
PubMed: 31689371
DOI: 10.1146/annurev-pathmechdis-012419-032544 -
Nature Medicine Oct 2021Germline SAMD9 and SAMD9L mutations (SAMD9/9L) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a...
Germline SAMD9 and SAMD9L mutations (SAMD9/9L) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L suppressed HEK293 cell growth, and mutations expressed in CD34 cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L MDS and exemplify the exceptional plasticity of hematopoiesis in children.
Topics: Adolescent; Bone Marrow Cells; Child; Child, Preschool; Clonal Evolution; Clonal Hematopoiesis; Female; GATA2 Transcription Factor; Germ-Line Mutation; HEK293 Cells; High-Throughput Nucleotide Sequencing; Humans; Infant; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Myelodysplastic Syndromes; Single-Cell Analysis; Tumor Suppressor Proteins
PubMed: 34621053
DOI: 10.1038/s41591-021-01511-6 -
Journal of Hematology & Oncology Feb 2021Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been...
Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. By parallel single-cell RNA-Seq, the transcriptomic phenotype of HCC was found to be related with genetic heterogeneity. For the first time we reconstructed the single-cell and single-variant clonal evolution in human liver cancer, and dissection of both genetic and phenotypic heterogeneity will facilitate better understanding of their relationship.
Topics: Carcinoma, Hepatocellular; Clonal Evolution; Humans; Liver Neoplasms; Mutation; Single-Cell Analysis; Tumor Cells, Cultured
PubMed: 33531041
DOI: 10.1186/s13045-021-01036-y -
Science (New York, N.Y.) Oct 2022Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic... (Review)
Review
Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
Topics: Humans; DNA Barcoding, Taxonomic; Clonal Evolution; Disease; Single-Cell Analysis
PubMed: 36227997
DOI: 10.1126/science.abm5874 -
Molecular Cancer Sep 2022Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for...
BACKGROUND
Multiple myeloma (MM) is a heterogeneous disease with different patterns of clonal evolution and a complex tumor microenvironment, representing a challenge for clinicians and pathologists to understand and dissect the contribution and impact of polyclonality on tumor progression.
METHODS
In this study, we established a global cell ecological landscape of the bone marrow (BM) from MM patients, combining single-cell RNA sequencing and single-molecule long-read genome sequencing data.
RESULTS
The malignant mutation event was localized to the tumor cell clusters with shared mutation of ANK1 and IFITM2 in all malignant subpopulations of all MM patients. Therefore, these two variants occur in the early stage of malignant clonal origin to mediate the malignant transformation of proplasmacytes or plasmacytes to MM cells. Tumor cell stemness index score and pseudo-sequential clonal evolution analysis can be used to divide the evolution model of MM into two clonal origins: types I and IX. Notably, clonal evolution and the tumor microenvironment showed an interactive relationship, in which the evolution process is not only selected by but also reacts to the microenvironment; thus, vesicle secretion enriches immune cells with malignant-labeled mRNA for depletion. Interestingly, microenvironmental modification exhibited significant heterogeneity among patients.
CONCLUSIONS
This characterization of the malignant clonal evolution pattern of MM at the single-cell level provides a theoretical basis and scientific evidence for a personalized precision therapy strategy and further development of a potential new adjuvant strategy combining epigenetic agent and immune checkpoint blockade.
Topics: Bone Marrow; Clonal Evolution; Humans; Immune Checkpoint Inhibitors; Membrane Proteins; Multiple Myeloma; RNA, Messenger; Tumor Microenvironment
PubMed: 36131282
DOI: 10.1186/s12943-022-01648-z -
Oncology Research and Treatment 2021Multiple myeloma is the second most common hematologic malignancy, which to date remains incurable despite advances in treatment strategies including the use of novel... (Review)
Review
BACKGROUND
Multiple myeloma is the second most common hematologic malignancy, which to date remains incurable despite advances in treatment strategies including the use of novel substances such as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies.
SUMMARY
The bone marrow-based disease is preceded by the 2 sequential premalignant conditions: monoclonal gammo-pathy of undetermined significance and smoldering myeloma. Plasma cell leukemia and extramedullary disease occur, when malignant clones lose their dependency on the bone marrow. Key genetic features of these plasma cell dyscrasias include chromosomal aberrations such as translocations and hyperdiploidy, which occur during error-prone physiologic processes in B-cell development. Next-generation sequencing studies have identified mutations in major oncogenic pathways and tumor suppressors, which contribute to the pathogenesis of multiple myeloma and have revealed insights into the clonal evolution of the disease, particularly along different lines of therapy. More recently, the importance of epigenetic alterations and the role of the bone marrow microenvironment, including immune and osteogenic cells, have become evident. Key Messages: We herein review the current knowledge of the pathogenesis of multiple myeloma, which is crucial for the development of novel targeted therapeutic strategies. These can contribute to the endeavor to make multiple myeloma a curable disease.
Topics: Antibodies, Monoclonal; Bone Marrow; Clonal Evolution; Humans; Immunomodulating Agents; Multiple Myeloma; Tumor Microenvironment
PubMed: 34749378
DOI: 10.1159/000520312 -
Cell Reports. Medicine Apr 2020Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of...
Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as C797S. amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, amplification, and fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies.
Topics: Acrylamides; Adult; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Clonal Evolution; Drug Resistance, Neoplasm; ErbB Receptors; Female; Genetic Heterogeneity; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Exome Sequencing; Young Adult
PubMed: 32483558
DOI: 10.1016/j.xcrm.2020.100007