57 research outputs found
Prognostically useful gene-expression profiles in acute myeloid leukemia
BACKGROUND: In patients with acute myeloid leukemia (AML) a combination of
methods must be used to classify the disease, make therapeutic decisions,
and determine the prognosis. However, this combined approach provides
correct therapeutic and prognostic information in only 50 percent of
cases. METHODS: We determined the gene-expression profiles in samples of
peripheral blood or bone marrow from 285 patients with AML using
Affymetrix U133A GeneChips containing approximately 13,000 unique genes or
expression-signature tags. Data analyses were carried out with Omniviz,
significance analysis of microarrays, and prediction analysis of
microarrays software. Statistical analyses were performed to determine the
prognostic significance of cases of AML with specific molecular
signatures. RESULTS: Unsupervised cluster analyses identified 16 groups of
patients with AML on the basis of molecular signatures. We identified the
genes that defined these clusters and determined the minimal numbers of
genes needed to identify prognostically important clusters with a high
degree of accuracy. The clustering was driven by the presence of
chromosomal lesions (e.g., t(8;21), t(15;17), and inv(16)), particular
genetic mutations (CEBPA), and abnormal oncogene expression (EVI1). We
identified several novel clusters, some consisting of specimens with
normal karyotypes. A unique cluster with a distinctive gene-expression
signature included cases of AML with a poor treatment outcome.
CONCLUSIONS: Gene-expression profiling allows a comprehensive
classification of AML that includes previously identified genetically
defined subgroups and a novel cluster with an adverse prognosis
High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL
It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.</p
DNA Methylation Signatures Identify Biologically Distinct Subtypes in Acute Myeloid Leukemia
Abstract: We hypothesized that DNA methylation distributes into specific patterns in cancer cells, which reflect critical biological differences. We therefore examined the methylation profiles of 344 patients with acute myeloid leukemia (AML). Clustering of these patients by methylation data segregated patients into 16 groups. Five of these groups defined new AML subtypes that shared no other known feature. In addition, DNA methylation profiles segregated patients with CEBPA aberrations from other subtypes of leukemia, defined four epigenetically distinct forms of AML with NPM1 mutations, and showed that established AML1-ETO, CBFb-MYH11, and PML-RARA leukemia entities are associated with specific methylation profiles. We report a 15 gene methylation classifier predictive of overall survival in an independent patient cohort (p < 0.001, adjusted for known covariates)
Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors
Testicular germ-cell tumors (TGCTs) of adolescents and adults originate
from intratubular germ cell neoplasia (ITGCN), which is composed of the
malignant counterparts of embryonal germ cells. ITGCN cells are
characterized, among others, by the presence of stem cell factor receptor
c-KIT. Once established, ITGCN will always progress to invasiveness.
Approximately 2.5-5% of patients with a TGCT will develop bilateral
disease and require complete castration, resulting in infertility, a need
for lifelong androgen replacement, and psychological stress. To date, the
only way to predict a contralateral tumor is surgical biopsy of the
contralateral testis to demonstrate ITGCN. We did a retrospective study of
224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three
independently collected series in Europe) for the presence of activating
c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three
unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In
the two wild-type bilateral tumors for which ITGCN was available, the
preinvasive cells contained the mutation. The mutations were somatic in
origin and identical in both tumors. We conclude that somatic activating
codon 816 c-KIT mutations are associated with development of bilateral
TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies
patients at risk for bilateral disease. These patients may undergo
tailored treatment to prevent the development of bilateral disease, with
retention of testicular hormonal function
Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis
Carta a l'editorWe studied the role of the recently identified CALR mutations in 141 patients with Budd-Chiari Syndrome (BCS) or portal vein thrombosis (PVT) in a large multinational cohort. A CALR mutation was present in one of the 141 patients (0.7%). This patient was previously diagnosed with primary myelofibrosis. This results in CALR positivity in one out of 44 (2.3%) patients with myeloproliferative neoplasm (MPN), and in one of 11 (9.1%) JAK2V617F negative patients diagnosed with MPN. We suggest that analysis of CALR mutations should be performed in JAK2V617F negative BCS and PVT patients..
Evolution of costs of inflammatory bowel disease over two years of follow-up
Background: With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. Methods and Findings: In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of € 7,835 in CD and € 3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02-3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61-13.86)). Conclusions: BD-related costs remained stable over two years. However, the proportion of anti-TNFrelated healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC
Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis
Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3-ITD-mutated AML. Thus, we suggest optimization of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations
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