Salisbury, United Kingdom
Salisbury, United Kingdom

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Barber J.,Wessex Regional Genetics Laboratory | Barber J.,Salisbury District Hospital | Cockwell A.,Wessex Regional Genetics Laboratory | Grant E.,St Georges Hospital Medical School | And 3 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2010

Karyotyping couples that have had recurrent miscarriages detects balanced rearrangements in carrier parents who can be offered prenatal cytogenetic analysis to prevent the birth of a subsequent child with an unbalanced rearrangement. In four UK centres, over periods of 5-30 years, balanced rearrangements were found in 406 out of 20 432 parents that had experienced miscarriage (1.9%), but only four unbalanced rearrangements were found after referral for prenatal diagnosis because of a balanced parental translocation ascertained for recurrent miscarriages. At an estimated cost of £3-4 million, these data raise doubts about the cost effectiveness of current policies on the routine karyotyping of couples experiencing repeated miscarriages. © RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology.


Mughal T.I.,Tufts University | Cross N.C.,Wessex Regional Genetics Laboratory | Padron E.,H. Lee Moffitt Cancer Center and Research Institute | Tiu R.V.,Cleveland Clinic | And 14 more authors.
Haematologica | Year: 2015

In the 2008 WHO classification, chronic myeloid malignancies that share both myelodysplastic and myeloproliferative features define the myelodysplastic/myeloproliferative group, which includes chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia, refractory anemia with ring sideroblasts and thrombocytosis, and myelodysplastic/myeloproliferative unclassified. With the notable exception of refractory anemia with ring sideroblasts and thrombocytosis, there is much overlap among the various subtypes at the molecular and clinical levels, and a better definition of these entities, an understanding of their biology and an identification of subtype-specific molecular or cellular markers are needed. To address some of these challenges, a panel comprised of laboratory and clinical experts in myelodysplastic/myeloproliferative was established, and four independent academic MDS/MPN workshops were held on: 9th March 2013, in Miami, Florida, USA; 6th December 2013, in New Orleans, Louisiana, USA; 13th June 2014 in Milan, Italy; and 5th December 2014 in San Francisco, USA. During these meetings, the current understanding of these malignancies and matters of biology, diagnosis and management were discussed. This perspective and the recommendations on molecular pathogenesis, diagnosis and clinical characterization for adult onset myelodysplastic/myeloproliferative is the result of a collaborative project endorsed and supported by the MDS Foundation. © 2015 Ferrata Storti Foundation.


Cross N.C.P.,University of Southampton | Cross N.C.P.,Wessex Regional Genetics Laboratory | White H.E.,Wessex Regional Genetics Laboratory | Muller M.C.,Universitatsmedizin Mannheim | And 2 more authors.
Leukemia | Year: 2012

The International Randomized Study of Interferon and STI571 (IRIS) demonstrated long-term cytogenetic responses in patients with chronic-phase chronic myeloid leukemia (CML-CP) treated with the tyrosine kinase inhibitor (TKI) imatinib. However, deep molecular responses (MRs), as measured by reductions in BCR-ABL transcript levels below the threshold of major MR, were achieved only by a small proportion of patients. With the advent of the second-generation TKIs nilotinib and dasatinib for the treatment of patients with newly diagnosed CML-CP, the proportion of patients who achieve the deepest levels of MR is likely to increase significantly. With these changes, the potential for patient eligibility in TKI cessations studies is becoming a more widely discussed topic and area for research. These developments highlight the need for robust, standardized and workable definitions of deep MRs. Specifically, it is critical that the measurement of MR is standardized in a manner to withstand both intra- and inter-laboratory variability, as well as new methodological developments. This review summarizes the relevant clinical background and proposes a framework within which standardization of MR can be taken forward. © 2012 Macmillan Publishers Limited.


Ernst T.,University of Southampton | Ernst T.,Universitatsklinikum Jena | Chase A.J.,University of Southampton | Chase A.J.,Wessex Regional Genetics Laboratory | And 24 more authors.
Nature Genetics | Year: 2010

Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies. © 2010 Nature America, Inc. All rights reserved.


Sharp A.J.,University of Geneva | Sharp A.J.,Mount Sinai School of Medicine | Migliavacca E.,University of Geneva | Migliavacca E.,Swiss Institute of Bioinformatics | And 14 more authors.
Genome Research | Year: 2010

The maternal and paternal genomes possess distinct epigenetic marks that distinguish them at imprinted loci. In order to identify imprinted loci, we used a novel method, taking advantage of the fact that uniparental disomy (UPD) provides a system that allows the two parental chromosomes to be studied independently. We profiled the paternal and maternal methylation on chromosome 15 using immunoprecipitation of methylated DNA and hybridization to tiling oligonucleotide arrays. Comparison of six individuals with maternal versus paternal UPD15 revealed 12 differentially methylated regions (DMRs). Putative DMRs were validated by bisulfite sequencing, confirming the presence of parent-of-origin-specific methylation marks. We detected DMRs associated with known imprinted genes within the Prader-Willi/Angelman syndrome region, such as SNRPN and MAGEL2, validating this as a method of detecting imprinted loci. Of the 12 DMRs identified, eight were novel, some of which are associated with genes not previously thought to be imprinted. These include a site within intron 2 of IGF1R at 15q26.3, a gene that plays a fundamental role in growth, and an intergenic site upstream of GABRG3 that lies within a previously defined candidate region conferring an increased maternal risk of psychosis. These data provide a map of parent-of-origin-specific epigenetic modifications on chromosome 15, identifying DNA elements that may play a functional role in the imprinting process. Application of this methodology to other chromosomes for which UPD has been reported will allow the systematic identification of imprinted sites throughout the genome. © 2010 by Cold Spring Harbor Laboratory Press.


Walz C.,Ludwig Maximilians University of Munich | Erben P.,Universitatsmedizin Mannheim | Ritter M.,Klinik fur Innere Medizin | Bloor A.,Christie Hospital National Health Service Foundation Trust | And 12 more authors.
Blood | Year: 2011

Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3+ myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of FLT3, previously reported in acute myeloid leukemia and potentially conferring resistance to sorafenib, was subsequently identified. Patient 2 was heavily pretreated according to the initial diagnosis of T-lymphoblastic lymphoma and died in sunitinib-induced pancytopenia. This report highlights the importance of a careful diagnostic workup for eosinophilia-associated neoplasms to evaluate the possibility of TK inhibitor therapy. © 2011 by The American Society of Hematology.


Chase A.,University of Southampton | Chase A.,Wessex Regional Genetics Laboratory | Bryant C.,University of Southampton | Bryant C.,Wessex Regional Genetics Laboratory | And 9 more authors.
Haematologica | Year: 2013

JAK2 fusion genes are rare but recurrent abnormalities associated with diverse, clinically heterogeneous hematologic malignancies. Here we assess the JAK1/2 inhibitor ruxolitinib as therapy for patients with JAK2-rearrangement associated myeloproliferative neoplasms (MPN). Ruxolitinib-treated Ba/F3 cells transformed to IL3 independence by ETV6-JAK2 showed reduced proliferation and survival (IC50 = 370 nM) compared with KG1A or Ba/F3 cells transformed by BCR-ABL1, SPBN1-FLT3 and ZMYM2-FGFR1 (IC50 > 10 mM for all). Inhibition was associated with reduced phosphorylation of ETV6-JAK2, ERK, STAT5 and AKT. Primary cell growth from 2 patients with JAK2 rearrangement and one patient with JAK2 amplification was assessed in methylcellulose assays. Reduced colony growth was seen for all patients in ruxolitinib-treated cultures compared with healthy controls (n=7). Fluorescence in situ hybridization showed reduced growth of JAK2-rearrangement positive colonies compared to JAK2-rearrangement negative colonies. Our data, therefore, provide evidence that ruxolitinib is a promising therapy for treatment of patients with JAK2 fusion genes. © 2013 Ferrata Storti Foundation.


PubMed | Ludwig Maximilians University of Munich, Wessex Regional Genetics Laboratory, University of Mannheim and Medical University of Vienna
Type: Journal Article | Journal: Leukemia | Year: 2016

We evaluated the impact of clinical and molecular characteristics on overall survival (OS) in 108 patients with indolent (n=41) and advanced systemic mastocytosis (SM) (advSM, n=67). Organomegaly was measured by magnetic resonance imaging-based volumetry of the liver and spleen. In multivariate analysis of all patients, an increased spleen volume 450ml (hazard ratio (HR), 5.2; 95% confidence interval (CI), (2.1-13.0); P=0.003) and an elevated alkaline phosphatase (AP; HR 5.0 (1.1-22.2); P=0.02) were associated with adverse OS. The 3-year OS was 100, 77, and 39%, respectively (P<0.0001), for patients with 0 (low risk, n=37), 1 (intermediate risk, n=32) or 2 (high risk, n=39) parameters. For advSM patients with fully available clinical and molecular data (n=60), univariate analysis identified splenomegaly 1200ml, elevated AP and mutations in the SRSF2/ASXL1/RUNX1 (S/A/R) gene panel as significant prognostic markers. In multivariate analysis, mutations in S/A/R (HR 3.2 (1.1-9.6); P=0.01) and elevated AP (HR 2.6 (1.0-7.1); P=0.03) remained predictive adverse prognostic markers for OS. The 3-year OS was 76 and 38%, respectively (P=0.0003), for patients with 0-1 (intermediate risk, n=28) or 2 (high risk, n=32) parameters. We conclude that splenomegaly, elevated AP and mutations in the S/A/R gene panel are independent of the World Health Organization classification and provide the most relevant prognostic information in SM patients.


PubMed | Universitatsmedizin Mannheim, Ludwig Maximilians University of Munich, Wessex Regional Genetics Laboratory and University Hospital Freiburg
Type: Case Reports | Journal: Annals of hematology | Year: 2016

The FIP1L1-PDGFRA (FP) fusion gene is identified in a substantial proportion of patients with eosinophilia-associated myeloproliferative neoplasms (MPN-eo) who subsequently achieve rapid and durable remissions on imatinib. In the initial diagnostic work-up of hypereosinophilia (HE), histologic and immunohistochemical evaluation of a bone marrow (BM) core biopsy is considered essential for the differentiation between reactive hypereosinophilia (HER), MPN-eo and hypereosinophilic syndrome (HES). We therefore retrospectively analysed the initial reports of BM core biopsies from 116 patients who were subsequently identified as FP positive (FP+, n=56) or FP negative/corticosteroid-responsive HER or HES (n=60). Compared to HER or HES, detection of FP was more frequently associated with increased numbers of blasts (11/56 vs. 2/60, p=0.007) and mast cells (23/33 vs. 7/23, p=0.006; with expression of CD25 [11/18 vs. 2/13, p=0.025]), and/or fibrosis (25/35 vs. 1/23, p<0.0001). In FP+ patients, HE was correctly associated with an underlying clonal haematologic disorder in only 36/56 (64%) of cases, but final BM diagnoses included a variety of diagnoses such as MPN-eo (n=15), acute myeloid leukaemia (n=8), systemic mastocytosis (n=6), chronic myeloid leukaemia (n=5) or unclassified MPN (n=2). We conclude that the final evaluation of BM core biopsies in the diagnostic work-up of HE should include comprehensive morphologic (stains for myeloid blast cells, mast cells and fibres) and genetic analyses before a final diagnosis is established.


Crolla J.A.,Wessex Regional Genetics Laboratory | Wapner R.,Columbia University | Van Lith J.M.M.,Leiden University
Prenatal Diagnosis | Year: 2014

What's already known about this topic? Chromosomal microarrays (CMA) are routinely used in postnatal genetic diagnosis. CMA is technically applicable in prenatal diagnosis. Pros and cons of routine use are discussed as follows: technical aspects and design of array, yield, interpretation of copy number variants and variances of unknown significance (VOUS), quality control regimens. What does this study add? Pros and cons of routine use are discussed as follows: technical aspects and design of array, yield, interpretation of copy number variants and variances of unknown significance (VOUS), quality control regimens. © 2013 John Wiley & Sons, Ltd.

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