In metabolism research, thermodynamics is usually used to determine the directionality of a reaction or the feasibility of a pathway. However, the relationship between thermodynamic potentials and ...fluxes is not limited to questions of directionality: thermodynamics also affects the kinetics of reactions through the flux-force relationship, which states that the logarithm of the ratio between the forward and reverse fluxes is directly proportional to the change in Gibbs energy due to a reaction (ΔrG'). Accordingly, if an enzyme catalyzes a reaction with a ΔrG' of -5.7 kJ/mol then the forward flux will be roughly ten times the reverse flux. As ΔrG' approaches equilibrium (ΔrG' = 0 kJ/mol), exponentially more enzyme counterproductively catalyzes the reverse reaction, reducing the net rate at which the reaction proceeds. Thus, the enzyme level required to achieve a given flux increases dramatically near equilibrium. Here, we develop a framework for quantifying the degree to which pathways suffer these thermodynamic limitations on flux. For each pathway, we calculate a single thermodynamically-derived metric (the Max-min Driving Force, MDF), which enables objective ranking of pathways by the degree to which their flux is constrained by low thermodynamic driving force. Our framework accounts for the effect of pH, ionic strength and metabolite concentration ranges and allows us to quantify how alterations to the pathway structure affect the pathway's thermodynamics. Applying this methodology to pathways of central metabolism sheds light on some of their features, including metabolic bypasses (e.g., fermentation pathways bypassing substrate-level phosphorylation), substrate channeling (e.g., of oxaloacetate from malate dehydrogenase to citrate synthase), and use of alternative cofactors (e.g., quinone as an electron acceptor instead of NAD). The methods presented here place another arrow in metabolic engineers' quiver, providing a simple means of evaluating the thermodynamic and kinetic quality of different pathway chemistries that produce the same molecules.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger ...and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.
Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies ...across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.
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•Evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases•Metastasis competence is afforded by chromosome complexity, but not driver mutation load•The hallmark genomic drivers of ccRCC metastasis are loss of 9p and 14q•Punctuated and branched evolution result in distinct patterns of metastases
A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.
The fundamental metabolic decision of a cell, the balance between respiration and fermentation, rests in part on expression of the mitochondrial genome (mtDNA) and coordination with expression of the ...nuclear genome (nuDNA). Previously we described mtDNA copy number depletion across many solid tumor types (Reznik et al., 2016). Here, we use orthogonal RNA-sequencing data to quantify mtDNA expression (mtRNA), and report analogously lower expression of mtRNA in tumors (relative to normal tissue) across a majority of cancer types. Several cancers exhibit a trio of mutually consistent evidence suggesting a drop in respiratory activity: depletion of mtDNA copy number, decreases in mtRNA levels, and decreases in expression of nuDNA-encoded respiratory proteins. Intriguingly, a minority of cancer types exhibit a drop in mtDNA expression but an increase in nuDNA expression of respiratory proteins, with unknown implications for respiratory activity. Our results indicate suppression of respiratory gene expression across many cancer types.
Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer ...cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.
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•A large clinico-genomic database to study metastatic patterns across 50 tumor types•Oncogenic alteration frequency and chromosomal instability are increased in metastases•Correlations between chromosomal instability and metastatic burden depend on cancer type•Genomic features associated with metastasis are identified for specific target organs
Clinico-genomic analysis of MSK-MET, a cohort of over 25,000 patients with metastasis across 50 cancer types, identifies somatic alterations associated with organ-specific metastasis and highlights that chromosomal instability correlates with metastatic burden in a cancer type-dependent manner.
Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue ...pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort.
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•ccRCC exhibit dysregulated oxidative phosphorylation and amino acid metabolism•Clinical progression of ccRCC manifested with elevated glutathione and dipeptides•Metabolomic clustering of human ccRCC identified distinct high- and low-risk subsets•Metabolograms visualize metabolomic, transcriptomic, and clinical data of ccRCC
Using metabolomic profiling, Ari Hakimi et al. show that clear cell renal cell carcinoma is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. They also develop metabolograms to allow integrating the TCGA transcriptomic data with their metabolomic data.
Tumorigenesis requires the re-organization of metabolism to support malignant proliferation. We examine how the altered metabolism of cancer cells is reflected in the rewiring of co-expression ...patterns among metabolic genes. Focusing on breast and clear-cell kidney tumors, we report the existence of key metabolic genes which act as hubs of differential co-expression, showing significantly different co-regulation patterns between normal and tumor states. We compare our findings to those from classical differential expression analysis, and counterintuitively observe that the extent of a gene's differential co-expression only weakly correlates with its differential expression, suggesting that the two measures probe different features of metabolism. Focusing on this discrepancy, we use changes in co-expression patterns to highlight the apparent loss of regulation by the transcription factor HNF4A in clear cell renal cell carcinoma, despite no differential expression of HNF4A. Finally, we aggregate the results of differential co-expression analysis into a Pan-Cancer analysis across seven distinct cancer types to identify pairs of metabolic genes which may be recurrently dysregulated. Among our results is a cluster of four genes, all components of the mitochondrial electron transport chain, which show significant loss of co-expression in tumor tissue, pointing to potential mitochondrial dysfunction in these tumor types.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The molecular foundations of Hürthle cell carcinoma (HCC) are poorly understood. Here we describe a comprehensive genomic characterization of 56 primary HCC tumors that span the spectrum of tumor ...behavior. We elucidate the mutational profile and driver mutations and show that these tumors exhibit a wide range of recurrent mutations. Notably, we report a high number of disruptive mutations to both protein-coding and tRNA-encoding regions of the mitochondrial genome. We reveal unique chromosomal landscapes that involve whole-chromosomal duplications of chromosomes 5 and 7 and widespread loss of heterozygosity arising from haploidization and copy-number-neutral uniparental disomy. We also identify fusion genes and disrupted signaling pathways that may drive disease pathogenesis.
•HCCs have a high number of mutations, several of which regulate translation•HCCs exhibit a high number of somatic recurrent mitochondrial mutations•HCCs have a unique chromosomal landscape, which predicts aggressive behavior•Several recurrent fusion genes, including TMEM233_PRKAB1, are identified
Ganly et al. elucidate recurrent mutations impacting the RTK/RAS/AKT/mTOR pathway, DNA damage/repair, epigenetic modifiers, TERT promoter, and the mitochondrial genome in Hürthle cell carcinoma (HCC). HCCs also display prevalent chromosome 5 and 7 duplications, loss of heterozygosity, and in-frame gene fusions.
Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural ...variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.
Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The ...Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.
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