More than 25% of patients with AML carry no mutations in genes known to be associated with leukemia. Analyses of genomes, transcriptomes, and methylomes of AML samples implicate mutations in ...cytogenetically normal AML and provide insight into the relationships among causative genes.
The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis.
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However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays
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(see Glossary). Targeted sequencing has identified recurrent mutations in
FLT3, NPM1, KIT, CEBPA,
and
TET2
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Massively parallel . . .
Clonal architecture in myeloproliferative neoplasms (MPNs) is poorly understood. Here we report genomic analyses of a patient with primary myelofibrosis (PMF) transformed to secondary acute myeloid ...leukemia (sAML). Whole genome sequencing (WGS) was performed on PMF and sAML diagnosis samples, with skin included as a germline surrogate. Deep sequencing validation was performed on the WGS samples and an additional sample obtained during sAML remission/relapsed PMF. Clustering analysis of 649 validated somatic single-nucleotide variants revealed four distinct clonal groups, each including putative driver mutations. The first group (including JAK2 and U2AF1), representing the founding clone, included mutations with high frequency at all three disease stages. The second clonal group (including MYB) was present only in PMF, suggesting the presence of a clone that was dispensable for transformation. The third group (including ASXL1) contained mutations with low frequency in PMF and high frequency in subsequent samples, indicating evolution of the dominant clone with disease progression. The fourth clonal group (including IDH1 and RUNX1) was acquired at sAML transformation and was predominantly absent at sAML remission/relapsed PMF. Taken together, these findings illustrate the complex clonal dynamics associated with disease evolution in MPNs and sAML.
Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumour progression. Here we describe the genomic analyses ...of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumour, a brain metastasis and a xenograft derived from the primary tumour. The metastasis contained two de novo mutations and a large deletion not present in the primary tumour, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumour mutations and displayed a mutation enrichment pattern that resembled the metastasis. Two overlapping large deletions, encompassing CTNNA1, were present in all three tumour samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared with the primary tumour indicate that secondary tumours may arise from a minority of cells within the primary tumour.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic ...mutations, of which 12 were in the coding sequences of genes and 52 were in conserved regions or regions with regulatory potential. Four mutations were found to be recurrent in AML, including mutations in
NRAS, NPM1, IDH1,
and a conserved region on chromosome 10.
A comparison of the genomic sequence of a tumor sample from a patient with acute myeloid leukemia (AML) and that of a normal skin sample from the same patient revealed an estimated 750 somatic mutations. Four mutations were found to be recurrent in AML.
Acute myeloid leukemia (AML) is a clonal hematopoietic disease caused by both inherited and acquired genetic alterations.
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Current AML classification and prognostic systems incorporate genetic information but are limited to known abnormalities that have previously been identified with the use of cytogenetics, array comparative genomic hybridization (CGH), gene-expression profiling, and the resequencing of candidate genes (see the Glossary).
The karyotyping of AML cells remains the most powerful predictor of the outcome in patients with AML and is routinely used by clinicians.
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As an adjunct to cytogenetic studies, small subcytogenetic amplifications and deletions can be identified with the use . . .
We present the discovery of KELT-21b, a hot Jupiter transiting the V = 10.5 A8V star HD 332124. The planet has an orbital period of P = 3.6127647 0.0000033 days and a radius of . We set an upper ...limit on the planetary mass of at confidence. We confirmed the planetary nature of the transiting companion using this mass limit and Doppler tomographic observations to verify that the companion transits HD 332124. These data also demonstrate that the planetary orbit is well-aligned with the stellar spin, with a sky-projected spin-orbit misalignment of . The star has K, , , and km s−1, the highest projected rotation velocity of any star known to host a transiting hot Jupiter. The star also appears to be somewhat metal poor and -enhanced, with and /Fe = 0.145 0.053; these abundances are unusual, but not extraordinary, for a young star with thin-disk kinematics like KELT-21. High-resolution imaging observations revealed the presence of a pair of stellar companions to KELT-21, located at a separation of 1 2 and with a combined contrast of with respect to the primary. Although these companions are most likely physically associated with KELT-21, we cannot confirm this with our current data. If associated, the candidate companions KELT-21 B and C would each have masses of ∼0.12 , a projected mutual separation of ∼20 au, and a projected separation of ∼500 au from KELT-21. KELT-21b may be one of only a handful of known transiting planets in hierarchical triple stellar systems.
Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using ...single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.
The Kilodegree Extremely Little Telescope (KELT) project has been conducting a photometric survey of transiting planets orbiting bright stars for over 10 years. The KELT images have a pixel scale of ...∼23″ pixel−1-very similar to that of NASA's Transiting Exoplanet Survey Satellite (TESS)-as well as a large point-spread function, and the KELT reduction pipeline uses a weighted photometric aperture with radius 3′. At this angular scale, multiple stars are typically blended in the photometric apertures. In order to identify false positives and confirm transiting exoplanets, we have assembled a follow-up network (KELT-FUN) to conduct imaging with spatial resolution, cadence, and photometric precision higher than the KELT telescopes, as well as spectroscopic observations of the candidate host stars. The KELT-FUN team has followed-up over 1600 planet candidates since 2011, resulting in more than 20 planet discoveries. Excluding ∼450 false alarms of non-astrophysical origin (i.e., instrumental noise or systematics), we present an all-sky catalog of the 1128 bright stars (6 < V < 13) that show transit-like features in the KELT light curves, but which were subsequently determined to be astrophysical false positives (FPs) after photometric and/or spectroscopic follow-up observations. The KELT-FUN team continues to pursue KELT and other planet candidates and will eventually follow up certain classes of TESS candidates. The KELT FP catalog will help minimize the duplication of follow-up observations by current and future transit surveys such as TESS.
We announce the discovery of KELT-16b, a highly irradiated, ultra-short period hot Jupiter transiting the relatively bright (V = 11.7) star TYC 2688-1839-1/KELT-16. A global analysis of the system ...shows KELT-16 to be an F7V star with K, , , , and . The planet is a relatively high-mass inflated gas giant with , , density g cm−3, surface gravity , and K. The best-fitting linear ephemeris is and day. KELT-16b joins WASP-18b, −19b, −43b, −103b, and HATS-18b as the only giant transiting planets with P < 1 day. Its ultra-short period and high irradiation make it a benchmark target for atmospheric studies by the Hubble Space Telescope, Spitzer, and eventually the James Webb Space Telescope. For example, as a hotter, higher-mass analog of WASP-43b, KELT-16b may feature an atmospheric temperature-pressure inversion and day-to-night temperature swing extreme enough for TiO to rain out at the terminator. KELT-16b could also join WASP-43b in extending tests of the observed mass-metallicity relation of the solar system gas giants to higher masses. KELT-16b currently orbits at a mere ∼1.7 Roche radii from its host star, and could be tidally disrupted in as little as a few ×105 years (for a stellar tidal quality factor of ). Finally, the likely existence of a widely separated bound stellar companion in the KELT-16 system makes it possible that Kozai-Lidov (KL) oscillations played a role in driving KELT-16b inward to its current precarious orbit.
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