Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum ...associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent increases in the frequency of Extreme Climate Events (ECEs) such as heatwaves and floods have been attributed to climate change, and could have pronounced ecosystem and evolutionary impacts ...because they provide little opportunity for organisms to acclimate or adapt. Here we synthesize information on a series of ECEs in Australia from 2011-2017 that led to well-documented, abrupt and extensive mortality of key marine habitat-forming organisms – corals, kelps, seagrasses and mangroves – along nearly more than 45% of the continental coastline of Australia. Coral bleaching occurred across much of northern Australia due to marine heatwaves affecting different regions in 2011, 2013, 2016 and 2017, while seagrass was impacted by anomalously high rainfall events in 2011 on both east and west tropical coasts. A marine heatwave off western Australia during the 2011 La Niña extended into temperate and subtropical regions, causing widespread mortality of kelp forests and seagrass communities at their northern distribution limits. Mangrove forests experienced high mortality during the 2016 El Niño across coastal areas of northern and north-western Australia due to severe water stress driven by drought and anomalously low mean sea levels. This series of ECEs reflects a variety of different events – marine heatwaves, intense rainfall from tropical storms, and drought. Their repeated occurrence and wide extent are consistent with projections of increased frequency and intensity of ECEs, and have broad implications elsewhere because similar trends are predicted globally. The unprecedented and widespread nature of these ECE impacts has likely produced substantial ecosystem-wide repercussions. Predictions from ecosystem models suggest that the widespread mortality of habitat-forming taxa will have long-term and in some cases irreversible consequences, especially if they continue to become more frequent or severe. The abrupt ecological changes that are caused by ECEs could have greater long-term impacts than slower warming that leads to gradual reorganisation and possible evolution and adaptation. ECEs are an emerging threat to marine ecosystems, and will require better seasonal prediction and mitigation strategies.
Detection and characterization of genomic structural variation are important for understanding the landscape of genetic variation in human populations and in complex diseases such as cancer. Recent ...studies demonstrate the feasibility of detecting structural variation using next-generation, short-insert, paired-end sequencing reads. However, the utility of these reads is not entirely clear, nor are the analysis methods with which accurate detection can be achieved. The algorithm BreakDancer predicts a wide variety of structural variants including insertion-deletions (indels), inversions and translocations. We examined BreakDancer's performance in simulation, in comparison with other methods and in analyses of a sample from an individual with acute myeloid leukemia and of samples from the 1,000 Genomes trio individuals. BreakDancer sensitively and accurately detected indels ranging from 10 base pairs to 1 megabase pair that are difficult to detect via a single conventional approach.
Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and ...acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.
Abstract
We present observations and analysis of the hostless and luminous Type Ia supernova 2022ilv, illustrating it is part of the 2003fg-like family, often referred to as super-Chandrasekhar ...(Ia-SC) explosions. The Asteroid Terrestrial-impact Last Alert System light curve shows evidence of a short-lived, pulse-like early excess, similar to that detected in another luminous Type Ia supernova (SN 2020hvf). The light curve is broad, and the early spectra are remarkably similar to those of SN 2009dc. Adopting a redshift of
z
= 0.026 ± 0.005 for SN 2022ilv based on spectral matching, our model light curve requires a large
56
Ni mass in the range 0.7–1.5
M
⊙
and a large ejecta mass in the range 1.6–2.3
M
⊙
. The early excess can be explained by fast-moving SN ejecta interacting with a thin, dense shell of circumstellar material close to the progenitor (∼10
13
cm) a few hours after the explosion. This may be realized in a double-degenerate scenario, wherein a white dwarf merger is preceded by the ejection of a small amount (∼10
−3
–10
−2
M
⊙
) of hydrogen and helium-poor tidally stripped material. A deep pre-explosion Pan-STARRS1 stack indicates no host galaxy to a limiting magnitude of
r
∼ 24.5. This implies a surprisingly faint limit for any host of
M
r
≳ −11, providing further evidence that these types of explosions occur predominantly in low-metallicity environments.
DNMT3A Mutations in Acute Myeloid Leukemia Ley, Timothy J; Ding, Li; Walter, Matthew J ...
The New England journal of medicine,
12/2010, Letnik:
363, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Whole-genome sequence analysis of cells from a patient with acute myeloid leukemia (AML) revealed a mutation in DNMT3A, which encodes an enzyme that methylates DNA. Subsequent analyses showed that ...DNMT3A was mutated in 33.7% of patients with AML with an intermediate-risk cytogenetic profile.
Whole-genome sequencing is an unbiased approach for discovering somatic variations in cancer genomes. We recently reported the DNA sequence and analysis of the genomes of two patients with acute myeloid leukemia (AML) with a normal karyotype.
1
,
2
We did not find new recurring mutations in the first study but did observe a recurrent mutation in
IDH1,
encoding isocitrate dehydrogenase 1, in the second study.
2
Subsequent work has confirmed and extended this finding, showing that mutations in
IDH1
and related gene
IDH2
are highly recurrent in patients with an intermediate-risk cytogenetic profile (20 to 30% frequency) and are associated with a . . .
We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and ...557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.
Whole-genome sequencing of samples from seven subjects with secondary acute myeloid leukemia identified somatic mutations. These data, together with genotype analysis of the antecedent ...myelodysplastic syndromes (MDS), revealed the clonal evolution of MDS and secondary AML.
The myelodysplastic syndromes, a heterogeneous group of diseases characterized by ineffective hematopoiesis, are the most common cause of acquired bone marrow failure in adults.
1
Secondary acute myeloid leukemia (AML) develops in approximately one third of persons with myelodysplastic syndromes.
2
Clinical discrimination between the myelodysplastic syndromes and secondary AML currently rests predominantly on cytomorphologic analysis, since patients with myelodysplastic syndromes have dysplastic hematopoiesis and a myeloblast count of less than 20%, whereas those with a myeloblast count of 20% or more have AML. Although considerable overlap exists between the spectrum of cytogenetic and molecular lesions seen in the two disorders, there . . .
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform ...an unbiased comprehensive screen to discover the somatic mutations in a sample from an individual with sAML and genotyped the loci containing these mutations in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (Ser34) in U2AF1 was recurrently present in 13 out of 150 (8.7%) subjects with de novo MDS, and we found suggestive evidence of an increased risk of progression to sAML associated with this mutation. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3' end of introns, and the alterations in U2AF1 are located in highly conserved zinc fingers of this protein. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This previously unidentified, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Genome-wide association studies (GWAS) have identified >500 common variants associated with quantitative metabolic traits, but in aggregate such variants explain at most 20-30% of the heritable ...component of population variation in these traits. To further investigate the impact of genotypic variation on metabolic traits, we conducted re-sequencing studies in >6,000 members of a Finnish population cohort (The Northern Finland Birth Cohort of 1966 NFBC) and a type 2 diabetes case-control sample (The Finland-United States Investigation of NIDDM Genetics FUSION study). By sequencing the coding sequence and 5' and 3' untranslated regions of 78 genes at 17 GWAS loci associated with one or more of six metabolic traits (serum levels of fasting HDL-C, LDL-C, total cholesterol, triglycerides, plasma glucose, and insulin), and conducting both single-variant and gene-level association tests, we obtained a more complete understanding of phenotype-genotype associations at eight of these loci. At all eight of these loci, the identification of new associations provides significant evidence for multiple genetic signals to one or more phenotypes, and at two loci, in the genes ABCA1 and CETP, we found significant gene-level evidence of association to non-synonymous variants with MAF<1%. Additionally, two potentially deleterious variants that demonstrated significant associations (rs138726309, a missense variant in G6PC2, and rs28933094, a missense variant in LIPC) were considerably more common in these Finnish samples than in European reference populations, supporting our prior hypothesis that deleterious variants could attain high frequencies in this isolated population, likely due to the effects of population bottlenecks. Our results highlight the value of large, well-phenotyped samples for rare-variant association analysis, and the challenge of evaluating the phenotypic impact of such variants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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