Population-based incidence of myeloid malignancies: fifteen years of epidemiological data in the province of Girona, Spain

Myeloid malignancies (MMs) are a heterogeneous group of hematologic malignancies presenting different incidence, prognosis and survival.1–3 Changing classifications (FAB 1994, WHO 2001 and WHO 2008) and few available epidemiological data complicate incidence comparisons.4,5 Taking this into account, the aims of the present study were: a) to calculate the incidence rates and trends of MMs in the Province of Girona, northeastern Spain, between 1994 and 2008 according to the WHO 2001 classification; and b) to predict the number of MMs cases in Spain during 2013. Data were extracted from the population-based Girona Cancer Registry (GCR) located in the north-east of Catalonia, Spain, and covering a population of 731,864 inhabitants (2008 census). Cases were registered according to the rules of the European Network for Cancer Registries and the Manual for Coding and Reporting Haematological Malignancies (HAEMACARE project). To ensure the complete coverage of MMs in the GCR, and especially myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS), a retrospective search was performed. The ICD-O-2 (1990) codes were converted into their corresponding ICD-O-3 (2000) codes, including MDS, polycythemia vera (PV) and essential thrombocythemia (ET) as malignant diseases. Results of crude rate (CR) and European standardized incidence rate (ASRE) were expressed per 100,000 inhabitants/year

Estudio de marcadores moleculares en neoplasias mieloproliferativas

Las neoplasias mieloproliferativas (NM) son un grupo de enfermedades clonales de la célula hematopoyética madre. Entre las NM clásicas se encuentran la policitemia vera (PV), la trombocitemia esencial (TE) y la mielofibrosis primaria (MFP). Durante muchos años el diagnóstico de estas patologías se hacía por exclusión utilizando biomarcadores de clonalidad poco específicos. En el año 2005, la descripción de la mutación JAK2V617F supuso un avance importante en el diagnóstico de estas patologías. Posteriormente, se han descrito mutaciones en otros genes como mutaciones en MPL, TET2, ASXL1, IDH1, IDH2, c-CBL, EZH2, IKZF1 y LNK, en distintas neoplasias mieloides y en porcentaje variable. Aun así, ninguno de estos genes son marcadores específicos de ninguna NM y todavía existe un porcentaje elevado de pacientes con TE y MFP sin un marcador de clonalidad conocido. Además, todos estos genes se han descrito como eventos genéticos implicados en la transformación de una NM a leucemia mieloide aguda. El objetivo de este proyecto fue estudiar varios marcadores moleculares en neoplasias mieloproliferativas Philadelphia negativas. En primer lugar, se estudió la modulación de la carga alélica JAK2V617F en pacientes con PV o TE que recibieron tratamiento citoreductor y a su vez se analizó la dinámica natural de la carga alélica en pacientes que no recibieron tratamiento. Posteriormente, se analizaron la presencia de alteraciones en los genes previamente mencionados, en distintos grupos de pacientes. En primer lugar, se analizó la presencia de mutaciones en TET2, ASXL1, IDH1, IDH2 y CBL en un grupo de pacientes JAK2 y MPL negativos, para determinar la frecuencia de alteraciones de estos genes en este grupo de pacientes y determinar su valor en el diagnóstico de estas patologías. En segundo lugar, se estudió la presencia de mutaciones en estos genes incluyendo EZH2, IKZF1 y LNK para estudiar la incidencia y el valor pronóstico de estas alteraciones en las NM que progresan a mielofibrosis.

The Oncoprotein BCL11A Binds to Orphan Nuclear Receptor TLX and Potentiates its Transrepressive Function

Nuclear orphan receptor TLX (NR2E1) functions primarily as a transcriptional repressor and its pivotal role in brain development, glioblastoma, mental retardation and retinopathologies make it an attractive drug target. TLX is expressed in the neural stem cells (NSCs) of the subventricular zone and the hippocampus subgranular zone, regions with persistent neurogenesis in the adult brain, and functions as an essential regulator of NSCs maintenance and self-renewal. Little is known about the TLX social network of interactors and only few TLX coregulators are described. To identify and characterize novel TLX-binders and possible coregulators, we performed yeast-two-hybrid (Y2H) screens of a human adult brain cDNA library using different TLX constructs as baits. Our screens identified multiple clones of Atrophin-1 (ATN1), a previously described TLX interactor. In addition, we identified an interaction with the oncoprotein and zinc finger transcription factor BCL11A (CTIP1/Evi9), a key player in the hematopoietic system and in major blood-related malignancies. This interaction was validated by expression and coimmunoprecipitation in human cells. BCL11A potentiated the transrepressive function of TLX in an in vitro reporter gene assay. Our work suggests that BCL11A is a novel TLX coregulator that might be involved in TLX-dependent gene regulation in the brain.

Usefulness of bone densitometry in postmenopausal women with clinically diagnosed vertebral fractures.

Objective: To analyse whether bone mineral density (BMD) assessment is required in postmenopausal women presenting with low trauma vertebral fracture. Methods: Women with vertebral fracture diagnosed over a 10 year period were recruited from our database. The following were excluded: (a) patients with high energy trauma; (b) patients with malignancies; (c) patients with a metabolic bone disease other than osteoporosis. All postmenopausal women were included in whom BMD had been evaluated at both the lumbar spine and femoral neck by dual energy x ray absorptiometry during the six months after the diagnosis. Patients with a potential cause of osteoporosis other than age and menopause were not considered. A total of 215 patients were identified. Results: The mean (SD) age of the patients was 65.9 (6.9) years. BMD at the lumbar spine was 0.725 (0.128) g/cm2 and the T score was ¿2.94 (1.22); BMD at the femoral neck was 0.598 (0.095) g/cm2 and the T score was ¿2.22 (0.89). The BMD of the patients was significantly lower than that of the general population at both the lumbar spine and femoral neck. When the lowest value of the two analysed zones was considered, six patients (3%) showed a normal BMD, 51 (23.5%) osteopenia, and 158 (73.5%) osteoporosis. The prevalence of osteoporosis at the femoral neck increased with age; it was 25% in patients under 60, 35% in patients aged 60¿70, and 60% in patients over 70. Conclusion: These results indicate that bone densitometry is not required in postmenopausal women with clinically diagnosed vertebral fractures if it is performed only to confirm the existence of a low BMD.

Epigenetic Activation of SOX11 in Lymphoid Neoplasms by Histone Modifications

Recent studies have shown aberrant expression of SOX11 in various types of aggressive B-cell neoplasms. To elucidate the molecular mechanisms leading to such deregulation, we performed a comprehensive SOX11 gene expression and epigenetic study in stem cells, normal hematopoietic cells and different lymphoid neoplasms. We observed that SOX11 expression is associated with unmethylated DNA and presence of activating histone marks (H3K9/14Ac and H3K4me3) in embryonic stem cells and some aggressive B-cell neoplasms. In contrast, adult stem cells, normal hematopoietic cells and other lymphoid neoplasms do not express SOX11. Such repression was associated with silencing histone marks H3K9me2 and H3K27me3. The SOX11 promoter of non-malignant cells was consistently unmethylated whereas lymphoid neoplasms with silenced SOX11 tended to acquire DNA hypermethylation. SOX11 silencing in cell lines was reversed by the histone deacetylase inhibitor SAHA but not by the DNA methyltransferase inhibitor AZA. These data indicate that, although DNA hypermethylation of SOX11 is frequent in lymphoid neoplasms, it seems to be functionally inert, as SOX11 is already silenced in the hematopoietic system. In contrast, the pathogenic role of SOX11 is associated with its de novo expression in some aggressive lymphoid malignancies, which is mediated by a shift from inactivating to activating histone modifications.

Survival of European patients diagnosed with lymphoid neoplasms in 2000-2002: results of the HAEMACARE project

The European Cancer Registry-based project on hematologic malignancies (HAEMACARE), setup to improve the availability and standardization of data on hematologic malignancies in Europe, used the European Cancer Registry-based project on survival and care of cancer patients (EUROCARE-4) database to produce a new grouping of hematologic neoplasma(defined by the International Classification of Diseases for Oncology, Third Edition and the 2001/2008 World Health Organization classifications) for epidemiological and public healthpurposes. We analyzed survival for lymphoid neoplasms in Europe by disease group, comparing survival between different European regions by age and sex. Design and Methods Incident neoplasms recorded between 1995 to 2002 in 48 population-based cancer registries in 20 countries participating in EUROCARE-4 were analyzed. The period approach was used to estimate 5-year relative survival rates for patients diagnosed in 2000-2002, who did not have 5years of follow up. Results: The 5-year relative survival rate was 57% overall but varied markedly between the definedgroups. Variation in survival within the groups was relatively limited across European regions and less than in previous years. Survival differences between men and women were small. The relative survival for patients with all lymphoid neoplasms decreased substantially after the age of 50. The proportion of ‘not otherwise specified’ diagnoses increased with advancing age.Conclusions: This is the first study to analyze survival of patients with lymphoid neoplasms, divided into groups characterized by similar epidemiological and clinical characteristics, providing a benchmarkfor more detailed analyses. This Europe-wide study suggests that previously noted differences in survival between regions have tended to decrease. The survival of patients with all neoplasms decreased markedly with age, while the proportion of ‘not otherwise specified’ diagnoses increased with advancing age. Thus the quality of diagnostic work-up and care decreased with age, suggesting that older patients may not be receiving optimal treatment