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Scientific Reports Jul 2023Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned... (Comparative Study)
Comparative Study
Naturally occurring canine cancers have remarkable similarities to their human counterparts. To better understand these similarities, we investigated 671 client-owned dogs from 96 breeds with 23 common tumor types, including those whose mutation profile are unknown (anal sac carcinoma and neuroendocrine carcinoma) or understudied (thyroid carcinoma, soft tissue sarcoma and hepatocellular carcinoma). We discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. As in human cancer, TP53 is the most commonly mutated gene, detected in 22.5% of canine tumors overall. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E (equivalent of V600E in humans) in urothelial carcinoma. Our findings better position canines as a translational model of human cancer to investigate a wide spectrum of targeted therapies.
Topics: Animals; Dogs; Oncogene Proteins; Mutation; Neoplasms; Humans; Antineoplastic Agents
PubMed: 37414794
DOI: 10.1038/s41598-023-37505-2 -
Genes & Development Aug 2023Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic... (Review)
Review
Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified translocations of transcription factor-coding genes in B-ALL, the extent of the targeting of regulatory networks in malignant transformation was not evident until the emergence of large-scale genomic analyses. There is now evidence that many B-ALL cases present with mutations in genes that encode transcription factors with critical roles in normal B-lymphocyte development. These include , , , and , all of which are targeted by translocations or, more commonly, partial inactivation in cases of B-ALL. Even though there is support for the notion that germline polymorphisms in the and genes predispose for B-ALL, the majority of leukemias present with somatic mutations in transcription factor-encoding genes. These genetic aberrations are often found in combination with mutations in genes that encode components of the pre-B-cell receptor or the IL-7/TSLP signaling pathways, all of which are important for early B-cell development. This review provides an overview of our current understanding of the molecular interplay that occurs between transcription factors and signaling events during normal and malignant B-lymphocyte development.
Topics: Humans; Transcription Factors; Gene Expression Regulation; Leukemia; Mutation; Translocation, Genetic; B-Lymphocytes
PubMed: 37673459
DOI: 10.1101/gad.349879.122 -
Genome Research Aug 2023Copy number variants (CNVs), duplications and deletions of genomic sequences, contribute to evolutionary adaptation but can also confer deleterious effects and cause...
Copy number variants (CNVs), duplications and deletions of genomic sequences, contribute to evolutionary adaptation but can also confer deleterious effects and cause disease. Whereas the effects of amplifying individual genes or whole chromosomes (i.e., aneuploidy) have been studied extensively, much less is known about the genetic and functional effects of CNVs of differing sizes and structures. Here, we investigated (yeast) strains that acquired adaptive CNVs of variable structures and copy numbers following experimental evolution in glutamine-limited chemostats. Although beneficial in the selective environment, CNVs result in decreased fitness compared with the euploid ancestor in rich media. We used transposon mutagenesis to investigate mutational tolerance and genome-wide genetic interactions in CNV strains. We find that CNVs increase mutational target size, confer increased mutational tolerance in amplified essential genes, and result in novel genetic interactions with unlinked genes. We validated a novel genetic interaction between different CNVs and that was common to multiple strains. We also analyzed global gene expression and found that transcriptional dosage compensation does not affect most genes amplified by CNVs, although gene-specific transcriptional dosage compensation does occur for ∼12% of amplified genes. Furthermore, we find that CNV strains do not show previously described transcriptional signatures of aneuploidy. Our study reveals the extent to which local and global mutational tolerance is modified by CNVs with implications for genome evolution and CNV-associated diseases, such as cancer.
Topics: Humans; DNA Copy Number Variations; Gene Dosage; Mutation; Genome; Saccharomyces cerevisiae; Aneuploidy
PubMed: 37652668
DOI: 10.1101/gr.277625.122 -
Leukemia May 2024The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the... (Review)
Review
The emergence of next generation sequencing and widespread use of mutational profiling in acute myeloid leukemia (AML) has broadened our understanding of the heterogeneous molecular basis of the disease. Since genetic sequencing has become a standard practice, several driver mutations have been identified. Accordingly, novel targeted therapeutic agents have been developed and are now approved for the treatment of subsets of patients that carry mutations in FLT3, IDH1, and IDH2 [1, 2]. The emergence of these novel agents in AML offers patients a new modality of therapy, and shifts treatment paradigms toward individualized medicine. In this review, we outline the role of IDH mutations in malignant transformation, focus in on a novel group of targeted therapeutic agents directed toward IDH1- and IDH2-mutant AML, and explore their impact on prognosis in patients with AML.
Topics: Isocitrate Dehydrogenase; Humans; Leukemia, Myeloid, Acute; Mutation; Prognosis; Disease Management; Molecular Targeted Therapy
PubMed: 38600315
DOI: 10.1038/s41375-024-02246-2 -
PLoS Biology Nov 2023The introduction of premature termination codons (PTCs), as a result of splicing defects, insertions, deletions, or point mutations (also termed nonsense mutations),...
The introduction of premature termination codons (PTCs), as a result of splicing defects, insertions, deletions, or point mutations (also termed nonsense mutations), lead to numerous genetic diseases, ranging from rare neuro-metabolic disorders to relatively common inheritable cancer syndromes and muscular dystrophies. Over the years, a large number of studies have demonstrated that certain antibiotics and other synthetic molecules can act as PTC suppressors by inducing readthrough of nonsense mutations, thereby restoring the expression of full-length proteins. Unfortunately, most PTC readthrough-inducing agents are toxic, have limited effects, and cannot be used for therapeutic purposes. Thus, further efforts are required to improve the clinical outcome of nonsense mutation suppressors. Here, by focusing on enhancing readthrough of pathogenic nonsense mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, we show that disturbing the protein translation initiation complex, as well as targeting other stages of the protein translation machinery, enhances both antibiotic and non-antibiotic-mediated readthrough of nonsense mutations. These findings strongly increase our understanding of the mechanisms involved in nonsense mutation readthrough and facilitate the development of novel therapeutic targets for nonsense suppression to restore protein expression from a large variety of disease-causing mutated transcripts.
Topics: Humans; Codon, Nonsense; Protein Biosynthesis; Anti-Bacterial Agents; Neoplasms
PubMed: 37943958
DOI: 10.1371/journal.pbio.3002355 -
Theoretical Population Biology Apr 2024In this paper, we investigate the consequences of dormancy in the 'rare mutation' and 'large population' regime of stochastic adaptive dynamics. Starting from an...
In this paper, we investigate the consequences of dormancy in the 'rare mutation' and 'large population' regime of stochastic adaptive dynamics. Starting from an individual-based micro-model, we first derive the Polymorphic Evolution Sequence of the population, based on a previous work by Baar and Bovier (2018). After passing to a second 'small mutations' limit, we arrive at the Canonical Equation of Adaptive Dynamics, and state a corresponding criterion for evolutionary branching, extending a previous result of Champagnat and Méléard (2011). The criterion allows a quantitative and qualitative analysis of the effects of dormancy in the well-known model of Dieckmann and Doebeli (1999) for sympatric speciation. In fact, quite an intuitive picture emerges: Dormancy enlarges the parameter range for evolutionary branching, increases the carrying capacity and niche width of the post-branching sub-populations, and, depending on the model parameters, can either increase or decrease the 'speed of adaptation' of populations. Finally, dormancy increases diversity by increasing the genetic distance between subpopulations.
Topics: Biological Evolution; Mutation
PubMed: 38325756
DOI: 10.1016/j.tpb.2024.02.003 -
PLoS Biology Apr 2024Endosymbiosis drives evolutionary innovation and underpins the function of diverse ecosystems. The mechanistic origins of symbioses, however, remain unclear, in part...
Endosymbiosis drives evolutionary innovation and underpins the function of diverse ecosystems. The mechanistic origins of symbioses, however, remain unclear, in part because early evolutionary events are obscured by subsequent evolution and genetic drift. This Essay highlights how experimental studies of facultative, host-switched, and synthetic symbioses are revealing the important role of fitness trade-offs between within-host and free-living niches during the early-stage evolution of new symbiotic associations. The mutational targets underpinning such trade-offs are commonly regulatory genes, such that single mutations have major phenotypic effects on multiple traits, thus enabling and reinforcing the transition to a symbiotic lifestyle.
Topics: Symbiosis; Ecosystem; Exercise; Genetic Drift; Mutation
PubMed: 38607979
DOI: 10.1371/journal.pbio.3002580 -
Blood Cancer Journal Sep 2023We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the...
We have previously recognized the genotypic and prognostic heterogeneity of U2AF1 mutations (MT) in myelofibrosis (MF) and myelodysplastic syndromes (MDS). In the current study, we considered 179 U2AF1-mutated patients with clonal cytopenia of undetermined significance (CCUS; n = 22), MDS (n = 108), MDS/acute myeloid leukemia (AML; n = 18) and AML (n = 31). U2AF1 variants included S34 (60%), Q157 (35%), and others (5%): corresponding mutational frequencies were 45%, 55%, and 0% in CCUS; 57%, 39%, and 4% in MDS; 61%, 33%, and 6% in MDS/AML; and 55%, 35% and 10% in AML (P = 0.17, 0.36 and 0.09), respectively. Concurrent mutations included ASXL1 (37%), BCOR (19%), RUNX1 (14%), TET2 (15%), DNMT3A (10%), NRAS/KRAS (8%), TP53 (8%), JAK2 (5.5%) and SETBP1 (5%). The two most frequent U2AF1 MT were S34F (n = 97) and Q157P (n = 46); concurrent MT were more likely to be seen with the latter (91% vs 74%; P = 0.01) and abnormal karyotype with the former (70% vs 62%; P = 0.05). U2AF1 S34F MT clustered with BCOR (P = 0.04) and Q157P MT with ASXL1 (P = 0.01) and TP53 (P = 0.03). The median overall survival (OS) in months was significantly worse in AML (14.2) vs MDS/AML (27.3) vs MDS (33.7; P = 0.001); the latter had similar OS with CCUS (30.0). In morphologically high-risk disease (n = 49), defined by ≥10% blood or bone marrow blasts (i.e., AML or MDS/AML), median OS was 14.2 with Q157P vs 37.1 months in the presence of S34F (P = 0.008); transplant-adjusted multivariable analysis confirmed the detrimental impact of Q157P (P = 0.01) on survival and also identified JAK2 MT as an additional risk factor (P = 0.02). OS was favorably affected by allogeneic hematopoietic stem cell transplantation (HR: 0.16, 95% CI; 0.04-0.61, P = 0.007). The current study defines the prevalence and co-mutational profiles of U2AF1 pathogenic variants in AML, MDS/AML, MDS, and CCUS, and suggests prognostic heterogeneity in patients with ≥10% blasts.
Topics: Humans; Splicing Factor U2AF; Prognosis; Myeloproliferative Disorders; Myelodysplastic Syndromes; Mutation; RNA-Binding Proteins; Leukemia, Myeloid, Acute
PubMed: 37735430
DOI: 10.1038/s41408-023-00922-7 -
Mathematical Biosciences Dec 2023Cancer occurs as a consequence of multiple somatic mutations that lead to uncontrolled cell growth. Mutual exclusivity and co-occurrence of mutations imply-but do not...
Cancer occurs as a consequence of multiple somatic mutations that lead to uncontrolled cell growth. Mutual exclusivity and co-occurrence of mutations imply-but do not prove-that mutations exert synergistic or antagonistic epistatic effects on oncogenesis. Knowledge of these interactions, and the consequent trajectories of mutation and selection that lead to cancer has been a longstanding goal within the cancer research community. Recent research has revealed mutation rates and scaled selection coefficients for specific recurrent variants across many cancer types. However, there are no current methods to quantify the strength of selection incorporating pairwise and higher-order epistatic effects on selection within the trajectory of likely cancer genotoypes. Therefore, we have developed a continuous-time Markov chain model that enables the estimation of mutation origination and fixation (flux), dependent on somatic cancer genotype. Coupling this continuous-time Markov chain model with a deconvolution approach provides estimates of underlying mutation rates and selection across the trajectory of oncogenesis. We demonstrate computation of fluxes and selection coefficients in a somatic evolutionary model for the four most frequently variant driver genes (TP53, LRP1B, KRAS and STK11) from 565 cases of lung adenocarcinoma. Our analysis reveals multiple antagonistic epistatic effects that reduce the possible routes of oncogenesis, and inform cancer research regarding viable trajectories of somatic evolution whose progression could be forestalled by precision medicine. Synergistic epistatic effects are also identified, most notably in the somatic genotype TP53 LRP1B for mutations in the KRAS gene, and in somatic genotypes containing KRAS or TP53 mutations for mutations in the STK11 gene. Large positive fluxes of KRAS variants were driven by large selection coefficients, whereas the flux toward LRP1B mutations was substantially aided by a large mutation rate for this gene. The approach enables inference of the most likely routes of site-specific variant evolution and estimation of the strength of selection operating on each step along the route, a key component of what we need to know to develop and implement personalized cancer therapies.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Mutation Rate; Mutation; Carcinogenesis; Genotype
PubMed: 37996064
DOI: 10.1016/j.mbs.2023.109091 -
Cancer Genetics Nov 2023Myeloid neoplasms represent a broad spectrum of hematological disorders for which somatic mutation status in key driver genes is important for diagnosis, prognosis and...
Myeloid neoplasms represent a broad spectrum of hematological disorders for which somatic mutation status in key driver genes is important for diagnosis, prognosis and treatment. Here we summarize the findings of a targeted, next generation sequencing laboratory developed test in 24,639 clinical myeloid samples. Data were analyzed comprehensively and as part of individual cohorts specific to acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN). Overall, 48,015 variants were detected, and variants were found in all 50 genes in the panel. The mean number of mutations per patient was 1.95. Mutation number increased with age (Spearman's rank correlation coefficient, ρ = 0.29, P < 0.0001) and was higher in patients with AML than MDS or MPN (Student's t-test, P < 0.0001). TET2 was the most common mutation detected (19.1% of samples; 4,695/24,639) including 7.7% (1,908/24,639) with multi-hit TET2 mutations. Mutation frequency was correlated between patients with cytopenias and MDS (Spearman's, ρ = 0.97, P < 2.2×10) with the MDS diagnostic gene SF3B1 being the only notable outlier. This large retrospective study shows the utility of NGS testing to inform clinical decisions during routine clinical care and highlights the mutational landscape of a broad population of myeloid patients.
Topics: Humans; Retrospective Studies; Mutation; Myeloproliferative Disorders; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
PubMed: 37586297
DOI: 10.1016/j.cancergen.2023.07.006