Unraveling the genetics of transformed splenic marginal zone lymphoma

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Large B-Cell, Diffuse; MutationLeucemia linfocítica crónica de células B; Linfoma de células B grandes difuso; MutaciónLeucèmia limfocítica crònica de cèl·lules B; Limfoma de cèl·lules B grans difús; MutacióThe genetic mechanisms associated with splenic marginal zone lymphoma (SMZL) transformation are not well defined. We studied 41 patients with SMZL that eventually underwent large B-cell lymphoma transformation. Tumor material was obtained either only at diagnosis (9 patients), at diagnosis and transformation (18 patients), and only at transformation (14 patients). Samples were categorized in 2 groups: (1) at diagnosis (SMZL, n = 27 samples), and (2) at transformation (SMZL-T, n = 32 samples). Using copy number arrays and a next-generation sequencing custom panel, we identified that the main genomic alterations in SMZL-T involved TNFAIP3, KMT2D, TP53, ARID1A, KLF2, 1q gains, and losses of 9p21.3 (CDKN2A/B) and 7q31-q32. Compared with SMZL, SMZL-T had higher genomic complexity, and higher incidence of TNFAIP3 and TP53 alterations, 9p21.3 (CDKN2A/B) losses, and 6p gains. SMZL and SMZL-T clones arose by divergent evolution from a common altered precursor cell that acquired different genetic alterations in virtually all evaluable cases (92%, 12 of 13 cases). Using whole-genome sequencing of diagnostic and transformation samples in 1 patient, we observed that the SMZL-T sample carried more genomic aberrations than the diagnostic sample, identified a translocation t(14;19)(q32;q13) present in both samples, and detected a focal B2M deletion due to chromothripsis acquired at transformation. Survival analysis showed that KLF2 mutations, complex karyotype, and International Prognostic Index score at transformation were predictive of a shorter survival from transformation (P = .001; P = .042; and P = .007; respectively). In summary, SMZL-T are characterized by higher genomic complexity than SMZL, and characteristic genomic alterations that could represent key players in the transformation event.This study was supported by Fundacion Asociación Española Contra el Cancer (AECC)/Centro de Investigación Biomédica en Red de Cancer (CIBERONC): PROYE18020BEA (S.B.), fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III “Cofinanciado por la Union Europea ´ and Fondos FEDER: European Regional Development Fund “Una manera de hacer Europa”: PI17/ 01061 (S.B.), PI19/00887 (A.L.-G. and E.G.), INT20/00050 (A.L.- G.), MaratO TV3-Cancer/201904-30 (S.B.), Generalitat de Catalunya Suport Grups de Recerca AGAUR (2021-SGR-01293 [S.B.] and 2021-SGR-01172 [E.C.]), and Ministerio de Ciencia e Innovacion (PID2021-123054OB-I00 [E.C.]). C.L. is supported by postdoctoral Beatriu de Pinos grant, Secretaria d´Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and by Marie Sklodowska-Curie COFUND program from H2020 (2018-BP-00055). E.C. is an Academia Researcher of the "Institucio Catalana de Recerca i Estudis Avançats" of the Generalitat de Catalunya. This work was mainly developed at the Centre Esther Koplowitz (CEK), Barcelona, Spain

Diferencias en el perfil reproductivo de mujeres autóctonas e inmigrantes residentes en Cataluña

ResumenObjetivoDescribir el perfil reproductivo en las mujeres autóctonas e inmigrantes residentes en Cataluña.MétodosLos abortos proceden del Registro de interrupción voluntaria del embarazo (IVE) del Departament de Salut, y los nacimientos y la población del Institut d’Estadística de Catalunya. Se han usado las variables «país de nacimiento» o «nacionalidad », según la fuente, para agrupar. Se analizan las tasas de fecundidad y aborto por edad, y las características sociodemográficas de las mujeres para el año 2005.ResultadosEl 20,8% de los 79.504 nacimientos y el 37,8% de las 16.798 IVE fueron de mujeres inmigrantes. El 14,2% de los embarazos de mujeres autóctonas y el 27,7% de los de mujeres inmigrantes terminan en aborto. Las tasa bruta de fecundidad y aborto es 1,4 y 3 veces superior, respectivamente, en las mujeres inmigrantes.ConclusionesHay importantes diferencias en las tasas y en las características sociodemográficas entre las mujeres autóctonas y las inmigrantes.AbstractObjectiveTo describe differences in reproductive patterns between autochthonous and immigrant women living in Catalonia (Spain).MethodsData on legal abortions were obtained from the abortions register in the Regional Ministry of Health, while data on births and the population were drawn from the Institute of Statistics of Catalonia. Depending on the source, the variables «country of birth» or «nationality» were used to compose the groups. Rates of fertility and abortion by age were computed for 2005 and the women's sociodemographic characteristics were analyzed.ResultsA total of 20.8% of the 79,504 births and 37.8% of the 16,798 abortions involved immigrant women, while 14.2% of pregnancies in autochthonous women and 27.7% of those in immigrant women terminated in abortion. Crude fertility and abortion rates were 1.4 and 3 times higher, respectively, in immigrant women.ConclusionsThere are important differences in abortion and fertility rates, as well as in social and demographic patterns, between autochthonous and immigrant women

Plataformes digitals per aprendre activa i cooperativament

e-status es una plataforma web que propone ejercicios a los estudiantes que se corrigen automáticamente. Un mismo ejercicio puede repetirse todas las veces que se desea, puesto que los datos son diferentes cada vez. Al acabar de resolver el ejercicio el estudiante obtiene una realimentación de su trabajo. La plataforma se ha utilizado en los últimos cursos en asignaturas de estadística de distintas carreras y presenta varias ventajas: fomenta el aprendizaje autónomo, permite adaptarse a los diferentes ritmos de aprendizaje y libera al profesor de la tarea rutinaria de la corrección. La plataforma supone un refuerzo práctico para el aprendizaje en disciplinas basadas en aplicación de técnicas cuantitativas y estudio de casos. Para evaluar la influencia y efectividad del uso de la herramienta en el resultado de la evaluación, se ha realizado un estudio con los estudiantes matriculados en el segundo cuatrimestre del curso 2007-2008 de la asignatura “Métodos estadísticos de la ingeniería I”, una asignatura troncal de la carrera de ingeniería industrial con 210 alumnos.Peer Reviewe

Prevalencia de la discapacidad en España por comunidades autónomas: el papel de los factores individuales y del entorno geográfico en su variabilidad

Fundamento: La prevalencia de discapacidad en la población general presenta una gran variabilidad geográfica, de manera que identificar aquellos factores que pudieran explicarla será importante para la planificación de políticas sociales. En este trabajo se analiza la variabilidad de la discapacidad por comunidades autónomas desde una doble vertiente, los factores individuales y del entorno. Métodos: Los datos proceden principalmente de la Encuesta de Discapacidad, Deficiencias y Estado de Salud de 1999 y del Inebase, ambas del Instituto Nacional de Estadística (INE). Se calculó la prevalencia de discapacidad simple y ajustada por edad de las CCAA. Se analizan los factores individuales asociados a la discapacidad mediante una regresión logística y los factores individuales y de la comunidad autónoma conjuntamente con una regresión logística de dos niveles. Resultados: La prevalencia de discapacidad muestra una diferencia máxima de 5,75 puntos entre las comunidades autónomas. En la regresión logística la comunidad de residencia fue estadísticamente significativa (OR: 3,35 en la de mayor prevalencia respecto a la de menor) junto con otras variables individuales: edad (OR de 40-64= 1,78 OR de 65-79= 1,87 y OR de >79= 3,34), sexo (OR mujer= 0,66), situación laboral (OR sin trabajo=2,25 OR amas casa/estudiante=1,39 y OR otros=2,03), estado de salud (OR regular= 1,69 OR malo/muy malo= 2,05) y enfermedades crónicas (OR 1-3=1,56 OR4-6=1,82 OR>6=2,59). En la regresión de dos niveles las variables individuales explican poca varianza (s=0,261) y ninguna de las variables relativas a las CCAA mejora el modelo. Conclusiones: Las características individuales no explican suficientemente la variabilidad de la discapacidad entre CCAA y no se han identificado variables del entorno que sean significativas.Background: The prevalence of disability shows a high geographical variability and the identification of factors that could explain these variations can be usuful to the heath and social welfare planning. Here the analysis of disability variations among autonomous regions in Spain is made taking into account individual and geographical setting factors together. Methods: Data come from the Spanish Disability, Impairment and Health Status survey of 1999 and from Inebase both of the National Institute for Statistics. The prevalence of disability crude and adjusted by age was calculated for each autonomous region. Individual factors related to disability are identified by means of a logistic regression. The analysis accounting for both, individual and geographical setting factors was performed by means of a logistic regression of two levels. Results: Disability prevalence showed a maximum difference of 5.75 points among regions. In a logistic regression the region of residence was statistically significant (OR: 3.35 in the highest rated region related to the lowest) beside several individual factors: age (OR 40-64= 1,78 OR 65-79= 1,87 and OR >79= 3,34), sex (OR women= 0,66), working status (OR unemployment=2,25 OR housewife/student=1,39 y OR other=2,03), health status (OR regular= 1,69 OR bad/very bad= 2,05) and chronic diseases (OR 1-3=1,56 OR 4-6=1,82 OR >6=2,59). Individual factors accounted for a very few variance at the two levels regression model (σ=0,261) and none of the regional variables improved the model. Conclusions: Individual factors do not explain enough the observed disability variations among the regions and none factor related to the geographical setting has been identified as statistically significant. analysis. Spain

Elaboració de material docent per a assignatures d'estadística industrial

La finalitat del projecte és elaborar material d'ajuda i suport a la docència per assignatures relacionades amb l'estadística industrial. Ens centrem fonamentalment en les assignatures “Mètodes estadístics de l’enginyeria 1”, d’enginyeria industrial, i “Estadística”, d’enginyera química, per la gran repercussió que tenen els canvis en aquestes assignatures (un total de 500 estudiants matriculats per any). El projecte es pot entendre com la continuació d’un altre projecte que va rebre un ajut de l’ICE i que es va desenvolupar durant el curs 2007-2008, titulat “Elaboració de material docent per a assignatures de control i millora de la qualitat” i coordinat per Lourdes Rodero de Lamo. La necessitat de creació de nou material sorgeix a partir de decidir canvis – alineats amb l’enfocament de l’EEES – en la metodologia docent. Els canvis venen motivats no només pel fet que aquestes dues assignatures entren en la fase pilot d’implantació de l’EEES a l’ETSEIB, sinó també – i sobretot – a partir de la constatació de fets que no ens agradaven als professors: poca assistència a classe, sensació de que els estudiants “no segueixen” l’assignatura, oblit ràpid del que s’ha aprés, etc.Peer Reviewe

Cyclin D1 overexpression induces global transcriptional downregulation in lymphoid neosplasms

Cyclin D1 is an oncogene frequently overexpressed in human cancers that has a dual function as cell cycle and transcriptional regulator, although the latter is widely unexplored. Here, we investigated the transcriptional role of cyclin D1 in lymphoid tumor cells with cyclin D1 oncogenic overexpression. Cyclin D1 showed widespread binding to the promoters of most actively transcribed genes, and the promoter occupancy positively correlated with the transcriptional output of targeted genes. Despite this association, the overexpression of cyclin D1 in lymphoid cells led to a global transcriptional downmodulation that was proportional to cyclin D1 levels. This cyclin D1-dependent global transcriptional downregulation was associated with a reduced nascent transcription and an accumulation of promoter-proximal paused RNA polymerase II (Pol II) that colocalized with cyclin D1. Concordantly, cyclin D1 overexpression promoted an increase in the Poll II pausing index. This transcriptional impairment seems to be mediated by the interaction of cyclin D1 with the transcription machinery. In addition, cyclin D1 overexpression sensitized cells to transcription inhibitors, revealing a synthetic lethality interaction that was also observed in primary mantle cell lymphoma cases. This finding of global transcriptional dysregulation expands the known functions of oncogenic cyclin D1 and suggests the therapeutic potential of targeting the transcriptional machinery in cyclin D1-overexpressing tumors

Insight into genetic predisposition to chronic lymphocytic leukemia from integrative epigenomics.

Genome-wide association studies have provided evidence for inherited genetic predisposition to chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms underlying CLL risk we analyze chromatin accessibility, active regulatory elements marked by H3K27ac, and DNA methylation at 42 risk loci in up to 486 primary CLLs. We identify that risk loci are significantly enriched for active chromatin in CLL with evidence of being CLL-specific or differentially regulated in normal B-cell development. We then use in situ promoter capture Hi-C, in conjunction with gene expression data to reveal likely target genes of the risk loci. Candidate target genes are enriched for pathways related to B-cell development such as MYC and BCL2 signalling. At 14 loci the analysis highlights 63 variants as the probable functional basis of CLL risk. By integrating genetic and epigenetic information our analysis reveals novel insights into the relationship between inherited predisposition and the regulatory chromatin landscape of CLL

Genomic complexity and IGHV mutational status are key predictors of outcome of chronic lymphocytic leukemia patients with TP53 disruption.

The clinical course of chronic lymphocytic leukemia (CLL) is extremely heterogeneous and while some patients achieve a normal lifespan, others succumb to the disease shortly after diagnosis. Recurrent chromosomal aberrations as detected by chromosome banding analysis (CBA) or fluorescent in situ hybridization (FISH) have a reproducible prognostic power in terms of response to therapy and survival.1–3 In particular, patients whose tumor cells harbor 17p deletions (17p-) are considered to have a shorter survival and, hence, high-risk CLL. This poor prognosis is, however, not universally true for all patients with 17p- CLL. Indeed, we and others have observed that some clinical-biological features, such as presence of B symptoms, advanced clinical stage, size of the 17p- clone, β2-microglobulin (β2M) concentration and IGH mutational status have a significant impact on the outcome of this subgroup of patients.4,5 Novel molecular studies have helped in the understanding of 17p- CLL. On one hand, TP53 mutations are present in more than 80% of cases with 17p deletion and in around 5% of patients without 17p deletion.6,7 On the other hand, next generation sequencing studies have revealed novel genetic aberrations such as NOTCH1 and SF3B1 mutations that have a negative impact on survival.8–10 Finally, genomic complexity, as defined by karyotyping1 or copy number (CN) arrays, has also been independently associated with disease transformation and poor outcome in patients with CLL.11,12 The aim of this study was to evaluate the prognostic value of concomitant molecular abnormalities in patients with CLL and TP53 aberrations as diagnosed by FISH, CBA or DNA sequencing