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2.
Blood ; 130(17): 1903-1910, 2017 10 26.
Article in English | MEDLINE | ID: mdl-28819011

ABSTRACT

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53 mutations (HR, 6.2; P < .0001) retained prognostic impact for overall survival (OS), whereas TP53 mutations (HR, 6.9; P < .0001) and MIPI-c high-risk (HR, 2.6; P = .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P < .0001). TP53 mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53 mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53 status, and that patients with TP53 mutations should be considered for experimental frontline trials exploring novel agents.


Subject(s)
Immunotherapy , Lymphoma, Mantle-Cell/drug therapy , Lymphoma, Mantle-Cell/genetics , Mutation/genetics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Bone Marrow/pathology , Cohort Studies , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Lymphoma, Mantle-Cell/pathology , Male , Middle Aged , Multivariate Analysis , Prognosis , Proportional Hazards Models
3.
Sci Rep ; 7(1): 6774, 2017 07 28.
Article in English | MEDLINE | ID: mdl-28754985

ABSTRACT

This is the first study to compare genome-wide DNA methylation profiles of sorted blood cells from myelofibrosis (MF) patients and healthy controls. We found that differentially methylated CpG sites located to genes involved in 'cancer' and 'embryonic development' in MF CD34+ cells, in 'inflammatory disease' in MF mononuclear cells, and in 'immunological diseases' in MF granulocytes. Only few differentially methylated CpG sites were common among the three cell populations. Mutations in the epigenetic regulators ASXL1 (47%) and TET2 (20%) were not associated with a specific DNA methylation pattern using an unsupervised approach. However, in a supervised analysis of ASXL1 mutated versus wild-type cases, differentially methylated CpG sites were enriched in regions marked by histone H3K4me1, histone H3K27me3, and the bivalent histone mark H3K27me3 + H3K4me3 in human CD34+ cells. Hypermethylation of selected CpG sites was confirmed in a separate validation cohort of 30 MF patients by pyrosequencing. Altogether, we show that individual MF cell populations have distinct differentially methylated genes relative to their normal counterparts, which likely contribute to the phenotypic characteristics of MF. Furthermore, differentially methylated CpG sites in ASXL1 mutated MF cases are found in regulatory regions that could be associated with aberrant gene expression of ASXL1 target genes.


Subject(s)
DNA Methylation/genetics , Epigenesis, Genetic , Mutation/genetics , Primary Myelofibrosis/genetics , Repressor Proteins/genetics , Aged , Aged, 80 and over , Antigens, CD34/metabolism , Cluster Analysis , CpG Islands/genetics , DNA-Binding Proteins/genetics , Dioxygenases , Female , Granulocytes/metabolism , Histones/metabolism , Humans , Male , Middle Aged , Oncogenes , Proto-Oncogene Proteins/genetics , Reproducibility of Results
4.
Am J Hematol ; 91(12): 1234-1238, 2016 12.
Article in English | MEDLINE | ID: mdl-27717004

ABSTRACT

Cytopenia is common in the elderly population and etiology may be difficult to assess. Here, we investigated the occurrence of mutations in patients with idiopathic cytopenia of undetermined significance and the usefulness in improving diagnostics. We included 60 patients with persistent cytopenia > 6 months without definite diagnosis of hematological neoplasm after routine assessment. Bone marrow material underwent a blinded morphology review and DNA was sequenced with a targeted 20 gene panel representing the most commonly mutated genes in myelodysplastic syndrome. Thirty seven (62%) patients carried at least one mutation at inclusion, and of these 95% carried a mutation in TET2, ASXL1, SRSF2, or DNMT3A. The most commonly mutated gene was TET2 observed in 43% of all patients. During one to eight years follow-up seven patients progressed to a myeloid neoplasm and six of these had a detectable mutation at study entry. Median time to progression was 53 months (range 10-78), and at time of progression each patient had at least two mutations detected. Mutations in TP53 and NRAS were not present in patients at inclusion, but identified as secondary hits triggering progression. The morphology review was concordant in 68% of all cases, and 93% of the cases reclassified into the group "highly suspicious for MDS" had a mutation. All patients who had a concordant review "highly suspicious for MDS" had at least two mutations detected. Overall, we show that morphology examination is challenging in this heterogeneous group and targeted sequencing helps identify patients at risk of progression. Am. J. Hematol. 91:1234-1238, 2016. © 2016 Wiley Periodicals, Inc.


Subject(s)
Disease Progression , Mutation , Myelodysplastic Syndromes/genetics , Pancytopenia/genetics , Adult , Aged , Aged, 80 and over , Bone Marrow Examination , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , DNA-Binding Proteins/genetics , Dioxygenases , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Pancytopenia/etiology , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Sequence Analysis, DNA , Serine-Arginine Splicing Factors/genetics
5.
PLoS One ; 7(3): e33100, 2012.
Article in English | MEDLINE | ID: mdl-22403733

ABSTRACT

Mutations in the Janus kinase 2 (JAK2) gene have become an important identifier for the Philadelphia-chromosome negative chronic myeloproliferative neoplasms. In contrast to the JAK2V617F mutation, the large number of JAK2 exon 12 mutations has challenged the development of quantitative assays. We present a highly sensitive real-time quantitative PCR assay for determination of the mutant allele burden of JAK2 exon 12 mutations. In combination with high resolution melting analysis and sequencing the assay identified six patients carrying previously described JAK2 exon 12 mutations and one novel mutation. Two patients were homozygous with a high mutant allele burden, whereas one of the heterozygous patients had a very low mutant allele burden. The allele burden in the peripheral blood resembled that of the bone marrow, except for the patient with low allele burden. Myeloid and lymphoid cell populations were isolated by cell sorting and quantitative PCR revealed similar mutant allele burdens in CD16+ granulocytes and peripheral blood. The mutations were also detected in B-lymphocytes in half of the patients at a low allele burden. In conclusion, our highly sensitive assay provides an important tool for quantitative monitoring of the mutant allele burden and accordingly also for determining the impact of treatment with interferon-α-2, shown to induce molecular remission in JAK2V617F-positive patients, which may be a future treatment option for JAK2 exon 12-positive patients as well.


Subject(s)
DNA Mutational Analysis/methods , Exons/genetics , Gene Frequency , Janus Kinase 2/genetics , Mutation/genetics , Real-Time Polymerase Chain Reaction/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young Adult
6.
Cancer Biol Ther ; 11(8): 732-9, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21330783

ABSTRACT

Malignancies in the upper gastrointestinal (UGI) tract are amongst the most aggressive cancers and only few treatment options exist. We have recently analysed data from a phase II trial where patients with UGI cancers were treated with erlotinib and bevacizumab. The combination therapy could not be recommended in an unselected population of patients with chemo-refractory UGI cancer. However, a subpopulation of patients did benefit from the therapy. In this prospectively planned biomarker study we investigated vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2) and epidermal growth factor receptor (EGFR) by immunohistochemistry and KRAS mutation status detected by PCR as potential predictors of effect of therapy. High VEGF-A expression was correlated to longer overall survival (HR: 0.8, 95%CI: 0.7-0.9) and high VEGFR-2 expression to shorter progression free survival (HR: 1.4, 95%CI: 1.0-1.9). EGFR expression and KRAS mutation status were not correlated to response or survival. We conclude that VEGF-A and VEGFR-2 could potentially be predictive markers in patients with UGI cancers treated with erlotinib and bevacizumab.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/metabolism , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/metabolism , Quinazolines/therapeutic use , Adult , Aged , Antibodies, Monoclonal, Humanized , Bevacizumab , Biomarkers, Tumor/genetics , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Female , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Humans , Male , Middle Aged , Mutation/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins p21(ras) , Survival Analysis , Treatment Outcome , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , ras Proteins/genetics
7.
J Med Virol ; 82(12): 2013-8, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20981787

ABSTRACT

Transmitted drug resistance (TDR) is a concern because it may reduce the efficacy of antiretroviral treatment. Plasma samples of 119 HIV-1-infected patients who were newly diagnosed at the Infectology Center of Latvia in 2005 and 2006 were analyzed by an in-house genotypic resistance assay to determine the prevalence of TDR in Latvia. TDR was identified using the WHO 2009 list of mutations for surveillance of TDR as implemented in the Stanford Calibrated Population Resistance tool. Neighbor-joining phylogenetic analyses were used to determine genetic subtype and investigate the relatedness of the sequences. Resistance testing was successful in 117 of 119 patients. The study population represented ∼20% of all patients that were diagnosed in Latvia in 2005 and 2006 and was well distributed between gender, transmission routes, and areas of residence. Four patients showed evidence of TDR, which represents a prevalence of TDR of 3.4% (95% CI: 0.9-8.5%). All four patients displayed single, but different resistance mutations (M46I, F53L, M41L, and G190A). All patients, except one, were predicted to respond well to standard first-line therapy in Latvia. The prevalence of TDR in Latvia was low, which partly may be due to the low proportion of HIV-1 patients who receive antiretroviral therapy. The results indicate that routine resistance testing in Latvia currently should be focused on patients who display treatment failure, rather than treatment naive patients.


Subject(s)
Anti-HIV Agents/pharmacology , Drug Resistance, Viral/genetics , HIV Infections/transmission , HIV Infections/virology , HIV-1/drug effects , Reverse Transcriptase Inhibitors/pharmacology , Adolescent , Adult , Aged , Child , Child, Preschool , Female , Genotype , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV-1/genetics , Humans , Infant , Infant, Newborn , Latvia/epidemiology , Male , Microbial Sensitivity Tests/methods , Middle Aged , Molecular Sequence Data , Mutation , Prevalence , Sequence Analysis, DNA , Young Adult
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