The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and ...histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.
In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the ...clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
The somatically acquired V600E mutation of the BRAF gene has been recently described as a molecular marker of hairy cell leukemia (HCL). We developed an allele-specific PCR for this mutation and ...studied 62 patients with HCL, 1 with HCL variant, 91 with splenic marginal zone lymphoma, 29 with Waldenström macroglobulinemia, and 57 with B-cell chronic lymphoproliferative disorders. The BRAF V600E mutation was detected in all HCL cases and in only 2 of the remaining 178 patients. These 2 subjects had B-cell chronic lymphoproliferative disorders that did not fulfill the diagnostic criteria for HCL. Despite the positive PCR finding, the mutation could not be detected by Sanger sequencing in these 2 cases, suggesting that it was associated with a small subclone. We conclude that the BRAF V600E mutation is present in all patients with HCL and that, in combination with clinical and morphologic features, represents a reliable molecular marker for this condition.
Our knowledge of the genetic basis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has considerably improved. To define genotype/phenotype relationships ...of clinical relevance, we studied 308 patients with MDS, MDS/MPN, or acute myeloid leukemia evolving from MDS. Unsupervised statistical analysis, including the World Health Organization classification criteria and somatic mutations, showed that MDS associated with SF3B1-mutation (51 of 245 patients, 20.8%) is a distinct nosologic entity irrespective of current morphologic classification criteria. Conversely, MDS with ring sideroblasts with nonmutated SF3B1 segregated in different clusters with other MDS subtypes. Mutations of genes involved in DNA methylation, splicing factors other than SF3B1, and genes of the RAS pathway and cohesin complex were independently associated with multilineage dysplasia and identified a distinct subset (51 of 245 patients, 20.8%). No recurrent mutation pattern correlated with unilineage dysplasia without ring sideroblasts. Irrespective of driver somatic mutations, a threshold of 5% bone marrow blasts retained a significant discriminant value for identifying cases with clonal evolution. Comutation of TET2 and SRSF2 was highly predictive of a myeloid neoplasm characterized by myelodysplasia and monocytosis, including but not limited to, chronic myelomonocytic leukemia. These results serve as a proof of concept that a molecular classification of myeloid neoplasms is feasible.
•Different driver mutations have distinct effects on phenotype of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN).•Accounting for driver mutations may allow a classification of these disorders that is considerably relevant for clinical decision-making.
Multiple myeloma is a biologically heterogenous plasma-cell disorder. In this study, we aimed at dissecting the functional impact on transcriptome of gene mutations, copy-number abnormalities (CNA), ...and chromosomal rearrangements (CR). Moreover, we applied a geno-transcriptomic approach to identify specific biomarkers for personalized treatments.
We analyzed 514 newly diagnosed patients from the IA12 release of the CoMMpass study, accounting for mutations in multiple myeloma driver genes, structural variants, copy-number segments, and raw-transcript counts. We performed an
drug sensitivity screen (DSS), interrogating the Cancer Dependency Map (DepMap) dataset after anchoring cell lines to primary tumor samples using the
algorithm.
Immunoglobulin translocations, hyperdiploidy and chr(1q)gain/amps were associated with the highest number of deregulated genes. Other CNAs and specific gene mutations had a lower but very distinct impact affecting specific pathways. Many recurrent genes showed a hotspot (HS)-specific effect. The clinical relevance of double-hit multiple myeloma found strong biological bases in our analysis. Biallelic deletions of tumor suppressors and chr(1q)-amplifications showed the greatest impact on gene expression, deregulating pathways related to cell cycle, proliferation, and expression of immunotherapy targets. Moreover, our
DSS showed that not only t(11;14) but also chr(1q)gain/amps and
inactivation predicted differential expression of transcripts of the BCL2 axis and response to venetoclax.
The multiple myeloma genomic architecture and transcriptome have a strict connection, led by CNAs and CRs. Gene mutations impacted especially with HS-mutations of oncogenes and biallelic tumor suppressor gene inactivation. Finally, a comprehensive geno-transcriptomic analysis allows the identification of specific deregulated pathways and candidate biomarkers for personalized treatments in multiple myeloma.
Active-edge planar radiation sensors Kenney, C.J.; Segal, J.D.; Westbrook, E. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
09/2006, Letnik:
565, Številka:
1
Journal Article
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Many systems in medicine, biology, high-energy physics, and astrophysics require large area radiation sensors. In most of these applications, minimizing the amount of dead area or dead material is ...crucial. We have developed a new type of silicon radiation sensor in which the device is active to within a few microns of the mechanical edge. Their perimeter is made by a plasma etcher rather than a diamond saw. Their edges can be defined and also passivated by growing, in an intermediate step, a field oxide on the side surfaces. In this paper, the basic architecture and results from a synchrotron beam test are presented.
Multiple myeloma (MM) has a highly heterogeneous genetic background, which complicates its molecular tracking over time. Nevertheless, each MM patient's malignant plasma cells (PCs) share unique ...V(D)J rearranged sequences at immunoglobulin loci, which represent ideal disease biomarkers. Because the tumor-specific V(D)J sequence is highly expressed in bulk RNA in MM patients, we wondered whether it can be identified by single-cell RNA sequencing (scRNA-seq). To this end we analyzed CD138
cells purified from bone marrow aspirates of 19 samples with PC dyscrasias by both a standard method based on bulk DNA and by an implementation of the standard 10x Genomics protocol to detect expressed V(D)J sequences. A dominant clonotype was easily identified in each sample, accounting on average for 83.65% of V(D)J-rearranged cells. Compared with standard methods, scRNA-seq analysis proved highly concordant and even more effective in identifying clonal productive rearrangements, by-passing limitations related to the misannealing of consensus primers in hypermutated regions. We next validated its accuracy to track 5 clonal cells with absolute sensitivity in a virtual sample containing 3180 polyclonal cells. This shows that single-cell V(D)J analysis may be used to find rare clonal cells, laying the foundations for functional single-cell dissection of minimal residual disease.
Test beam results of 3D silicon pixel sensors for the ATLAS upgrade Grenier, P.; Alimonti, G.; Barbero, M. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2011, Letnik:
638, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Results on beam tests of 3D silicon pixel sensors aimed at the ATLAS Insertable B-Layer and High Luminosity LHC (HL-LHC) upgrades are presented. Measurements include charge collection, tracking ...efficiency and charge sharing between pixel cells, as a function of track incident angle, and were performed with and without a 1.6
T magnetic field oriented as the ATLAS inner detector solenoid field. Sensors were bump-bonded to the front-end chip currently used in the ATLAS pixel detector. Full 3D sensors, with electrodes penetrating through the entire wafer thickness and active edge, and double-sided 3D sensors with partially overlapping bias and read-out electrodes were tested and showed comparable performance.
Smoldering multiple myeloma (SMM) is an asymptomatic disorder of clonal bone marrow (BM) plasma cells (PCs) in between the premalignant condition known as monoclonal gammopathy of undetermined ...significance and overt multiple myeloma (MM). It is characterized by a deep biological heterogeneity that is reflected in a markedly variable progression risk among patients. Recently proposed risk stratification models mainly rely on indirect markers of disease burden and are unable to identify cases in whom clonal PCs have already undergone the “malignant switch” but major clonal expansion has not occurred yet. In the last years, the application of next-generation sequencing (NGS) techniques has led to profound advances in the understanding of the molecular bases of SMM progression, and in all likelihood, it will contribute to the needed improvement of SMM prognostication. In this Review, we describe the recent advances in characterizing the genomic landscape of SMM and intrinsic determinants of its progression, highlighting their implications in terms of understanding of tumor evolution and prognostication. We also review the main studies investigating the role of the microenvironment in this early disease stage. Finally, we mention the results of the first randomized clinical trials and discuss the potential clinical translability of the genomic insights.
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