una mirada desde las Ciencias de la Conducta

Este libro es el resultado de los trabajos presentados en el 1er Congreso Internacional "Convivencia y bienestar con sentido humanista para una cultura de paz"

Caracterización genética de la micosis fungoide tumoral

Los linfomas cutáneos primarios de células T (LCPCT) son un grupo heterogéneo de linfomas no-Hodgkin que se caracterizan por la presencia de linfocitos atípicos en la piel. En el presente trabajo se ha analizado el perfil genético de la micosis fungoide tumoral (MFt) para conocer las alteraciones más frecuentes y su posible función como marcadores pronósticos. Por otra parte, se ha realizado un estudio paralelo para conocer el estatus de los genes del receptor de células T (TCR). Se estudiaron un total de 41 MFt, 13 síndromes de Sézarys (SS) y 6 linfomas cutáneos anaplásicos de célula grande CD30+ (LCACG-CD30+). Se aplicaron las técnicas de microarrays de hibridación genómica comparada (oligoarrayCGH) e hibridación in situ fluorescente (FISH) para los genes del TCR. El análisis de oligoarrayCGH reveló que un 78% presentaron alteraciones genéticas. Las alteraciones más frecuentes fueron las ganancias de 7q33.3q35, 17q21.1, 8q24.21, 9q34, 10p14 y 1q31.2q32.2, y las pérdidas de 9p21.3, 9q31.2, 17p13.1, 13q14.11, 6q21.3, 10p11.22, 16q23.2 y 16q24.3. El análisis de la inestabilidad genética permitió segregar a las MFt en dos grupos, uno genéticamente estable (0-5 alteraciones) y otro genéticamente inestable (>5 alteraciones). Además, se ha observado que el grupo genéticamente inestable se asociaba a la ganancia del cromosoma 7q. Finalmente, se ha observado que pertenecer al grupo genéticamente inestable así como presentar deleciones de 9p21.3, 10q26qter y ganancia en 8q24.21 se asociaba a una peor supervivencia. El análisis de los genes del TCR ha mostrado que las translocaciones de TCRAD, TCRB y TCRG no es un evento genético frecuente en los LCPCT. Sin embargo, se han observado ganancias en el número de copias de las sondas TCRB (7q34) y TCRG (7p14) en 3/6 MFt y 3/13 SS, lo que confirma los resultados previamente observados mediante las técnicas de oligoarrayCGH y citogenética convencional. De este estudio se concluye: 1. Nuestros datos confirman que la MFt presenta un perfil genético caracterizado por las ganancias de 7q, 17q, 8q, 9q, 10p y 1q, y las pérdidas de 9p, 9q, 17p, 13q, 6q, 10p y 16q. 2. Las alteraciones estructurales de los loci del TCR no son una característica genética de los LCPCT. Sin embargo, no se excluye su papel patogénico en los LCPCT. 3. Se ha definido el perfil de inestabilidad genético de la MFt y se ha observado la presencia de dos grupos, un grupo estable y otro inestable. Además, se ha observado una asociación significativa de la ganancia del cromosoma 7q con el perfil genéticamente inestable, lo que sugiere un importante papel patogénico de esta región en este subgrupo de MFt. 4. Respecto a los marcadores pronóstico, las pérdidas de 9p21.3 y 10q26qter, y la ganancia de 8q24.21, así como pertenecer al grupo genéticamente inestable se han asociado a un pronóstico desfavorable. Por otra parte, la edad superior a los 60 años en el momento del diagnóstico y el hecho de presentar lesiones cutáneas en más de dos localizaciones también se han asociado a una peor supervivencia. 5. Se ha observado que las MFt que presentaban infiltración en sangre periférica, presentaban alteraciones similares a las halladas en el SS en estudios previos lo que sugiere la existencia de una firma genética común para los SS de novo y los SS con una MF previa. Con respecto a los LCACG-CD30+, se confirma que ambas entidades son diferentes, no sólo en sus características clínicas sino también en sus perfiles genéticos.Primary cutaneous T cells lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas characterized by the presence of atypical lymphocytes in the skin. This work analyzed exhaustively the genomic profile of the tumoral stage mycosis fungoides (MFt) to find the most frequent alterations and their possible role as prognostic markers, as well as, to compare MFt genetic profile with other CTCL (specifically, Sézary syndrome [SS] and cutaneous anaplastic large cell lymphoma-CD30+ [cALCL-CD30+]). Moreover, there has been a parallel study to know the status of the genes of T cell receptor (TCR). We studied a total of 41 MFt, 13 SS and 6 cALCL-CD30+ using oligonucleotide array comparative genomic hybridization (oligoarrayCGH) and fluorescence in situ hybridization (FISH) techniques. Among the 41 MFt, 78% had genetic alterations. The most frequent alterations were gains of 7q33.3q35, 17q21.1, 8q24.21, 9q34, 10p14 and 1q31.2q32.2, and losses of 9p21.3, 9q31.2, 17p13.1, 13q14.11, 6q21.3, 10p11.22, 16q23.2 and 16q24.3. We also performed a genetic instability analysis and it has been observed that MFt segregate into two groups, a genetically stable (0-5 changes) and a genetically unstable (> 5 changes). It has also been observed that genetically unstable group was related to the presence of the gain of 7q. Regarding prognostic markers, deletion of 9p21.3, 10q26qter and 8q24.21 gain and to belong to the genetically unstable group was associated with a poor overall survival. On the other hand, TCR genes analyses showed that TCRAD, TCRB and TCRG translocations are not a frequent event in CTCL. However, we have observed extra signal FISH copies of TCRB (7q34) and TCRG (7p14) probes in 3/6 MFt and 3/13 SS, confirming our results previously observed by conventional cytogenetics and oligoarrayCGH techniques. This study concludes: 1. Our results confirm a MFt genomic profile characterized by gains of 7q, 17q, 8q, 9q, 10p y 1q, and losses of 9p, 9q, 17p, 13q, 6q, 10p y 16q regions. 2. TCR loci structural alterations are not a genetic characteristic of CTCLs. 3. We have defined the genomic instability of MFT and we observed the presence of two distinct groups: one called genetically stable and a second group called genetically unstable, characterized by the presence of numerous genetic changes. It has also observed a significant association of chromosome 7q gain with the genetically unstable group, suggesting an important pathogenic role of this region in this subset of MFT. 4. We have observed that losses of 9p21.3 and 10q26qter regions and the gain of the 8q24.21 region as well as belonging to the genetically unstable group have been associated with a poor prognosis. With regard to clinical characteristics, age over 60 years at diagnosis and presenting skin lesions in more than two locations have also been associated with poorer survival. 5. The comparison between MFt and SS genomic profiles has shown that MFt patients with peripheral blood involvement showed similar changes to those found in the SS in previous studies. These findings suggest the existence of a common genetic signature for de novo SS and SS with a previous MF. Regarding cALCL-CD30+, we confirmed that both entities are different not only in its clinical features but also on their genetic profiles

Multivariate Data Retrieval Modified by Random Noise using Lattice Autoassociative Memories with Eroded or Dilated Input Residuals

Lattice associative memories were proposed as an alternative approach to work with a set of associated vector pairs for which the storage and retrieval stages are based in the theory of algebraic lattices. Several techniques have been established to deal with the problem of binary or real valued vector recall from corrupted inputs. This paper presents a thresholding technique coupled with statistical correlation pattern index search to enhance the recall performance of lattice auto-associative memories for multivariate data inputs degraded by random noise. By thresholding a given noisy input, a lower bound is generated to produce an eroded noisy version used to boost the min-lattice auto-associative memory inherent retrieval capability. Similarly, an upper bound is generated to obtain a dilated noisy version used to enhance the max-lattice auto-associave memory response. A self contained theoretical foundation is provided including a visual example of a multivariate data set composed of grayscale images that show the increased retrieval capability of this type of associative memories

Caracterización genética de la micosis fungoide tumoral

Los linfomas cutáneos primarios de células T (LCPCT) son un grupo heterogéneo de linfomas no-Hodgkin que se caracterizan por la presencia de linfocitos atípicos en la piel. En el presente trabajo se ha analizado el perfil genético de la micosis fungoide tumoral (MFt) para conocer las alteraciones más frecuentes y su posible función como marcadores pronósticos. Por otra parte, se ha realizado un estudio paralelo para conocer el estatus de los genes del receptor de células T (TCR).5. Se ha observado que las MFt que presentaban infiltración en sangre periférica, presentaban alteraciones similares a las halladas en el SS en estudios previos lo que sugiere la existencia de una firma genética común para los SS de novo y los SS con una MF previa. Con respecto a los LCACG-CD30+, se confirma que ambas entidades son diferentes, no sólo en sus características clínicas sino también en sus perfiles genéticos. 5 changes). It has also been observed that genetically unstable group was related to the presence of the gain of 7q. Regarding prognostic markers, deletion of 9p21.3, 10q26qter and 8q24.21 gain and to belong to the genetically unstable group was associated with a poor overall survival. On the other hand, TCR genes analyses showed that TCRAD, TCRB and TCRG translocations are not a frequent event in CTCL. However, we have observed extra signal FISH copies of TCRB (7q34) and TCRG (7p14) probes in 3/6 MFt and 3/13 SS, confirming our results previously observed by conventional cytogenetics and oligoarrayCGH techniques. This study concludes: 1. Our results confirm a MFt genomic profile characterized by gains of 7q, 17q, 8q, 9q, 10p y 1q, and losses of 9p, 9q, 17p, 13q, 6q, 10p y 16q regions. 2. TCR loci structural alterations are not a genetic characteristic of CTCLs. 3. We have defined the genomic instability of MFT and we observed the presence of two distinct groups: one called genetically stable and a second group called genetically unstable, characterized by the presence of numerous genetic changes. It has also observed a significant association of chromosome 7q gain with the genetically unstable group, suggesting an important pathogenic role of this region in this subset of MFT. 4. We have observed that losses of 9p21.3 and 10q26qter regions and the gain of the 8q24.21 region as well as belonging to the genetically unstable group have been associated with a poor prognosis. With regard to clinical characteristics, age over 60 years at diagnosis and presenting skin lesions in more than two locations have also been associated with poorer survival. 5. The comparison between MFt and SS genomic profiles has shown that MFt patients with peripheral blood involvement showed similar changes to those found in the SS in previous studies. These findings suggest the existence of a common genetic signature for de novo SS and SS with a previous MF. Regarding cALCL-CD30+, we confirmed that both entities are different not only in its clinical features but also on their genetic profiles

Comprehensive characterization of a novel, oncogenic and targetable SEPTIN6::ABL2 fusion in T-ALL

Altres ajuts: Fundación Ramón Areces, CIVP19S7917; Comunidad de Madrid, B2017/BMD-3778; Asociación Española Contra el Cáncer, PROYE18054PIRI, LABAE20049RODR; Instituto de Investigación Sanitaria Fundación Jiménez Díaz; Fundación Ramón Areces; Banco de Santander

Redefining the high‐grade B cell lymphoma with double/triple rearrangements of MYC and BCL2/BCL6 genes. Learning from a case report

We report a patient initially diagnosed with a triple hit high‐grade B cell lymphoma (HGBL‐TH), in which further morphologic, immunohistochemical, and next‐generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC‐DLBCL) with BCL2/BCL6 gene translocations, PVT1‐deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break‐apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH‐lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double‐hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas

Lymphoplasmacytic lymphoma associated with diffuse large B-cell lymphoma: Progression or divergent evolution?

AimLymphoplasmacytic lymphoma (LPL) is an indolent mature B-cell-neoplasm with involvement of the bone marrow. At least 90% of LPLs carry MYD88-L265P mutation and some of them (~10%) transform into diffuse large B-cell-lymphoma (DLBCL).Material and methodsOver the past 15 years we have collected 7 cases where the both LPL and DLBCL were diagnosed in the same patient. Clinical records, analytical data and histopathological specimens were reviewed. FISH studies on paraffin-embedded tissue for MYC, BCL2 and BCL6 genes were performed, as well as MYD88-L265P mutation and IGH rearrangement analysis by PCR. A mutational study was done by massive next generation sequencing (NGS).ResultsThere were 4 women and 3 men between 36-91 years of age. Diagnoses were made simultaneously in 4 patients. In two cases the LPL appeared before the DLBCL and in the remaining case the high-grade component was discovered 5 years before the LPL. In 6 cases both samples shared the MYD88-L265P mutation. IGH rearrangement analysis showed overlapping features in two of 6 cases tested. Mutational study was evaluable in three cases for both samples showing shared and divergent mutations.ConclusionsThese data suggest different mechanisms of DLBCL development in LPL patients

Novel Candidate <i>loci</i> and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing

The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development (CHEK2 and RAD54L). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes (NFATC2 and TC2N). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies (GATA1, MSH4 and PRF1). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families

Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing

The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development (CHEK2 and RAD54L). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes (NFATC2 and TC2N). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies (GATA1, MSH4 and PRF1). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families

Patients with chronic lymphocytic leukemia and complex karyotype show an adverse outcome even in absence of TP53/ATM FISH deletions

Genomic complexity identified by chromosome banding analysis (CBA) predicts a worse clinical outcome in CLL patients treated either with standard or new treatments. Herein, we analyzed the clinical impact of complex karyotypes (CK) with or without high-risk FISH deletions (ATM and/or TP53, HR-FISH) in a cohort of 1045 untreated MBL/CLL patients. In all, 99/1045 (9.5%) patients displayed a CK. Despite ATM and TP53 deletions were more common in CK (25% vs 7%; P < 0.001; 40% vs 5%; P < 0.001, respectively), only 44% (40/90) patients with TP53 deletions showed a CK. CK group showed a significant higher two-year cumulative incidence of treatment (48% vs 20%; P < 0.001), as well as a shorter overall survival (OS) (79 mo vs not reached; P < 0.001). When patients were categorized regarding CK and HR-FISH, those with both characteristics showed the worst median OS (52 mo) being clearly distinct from those non-CK and non-HR-FISH (median not reached), but no significant differences were detected between cases with only CK or HR-FISH. Both CK and TP53 deletion remained statistically significant in the multivariate analysis for OS. In conclusion, CK group is globally associated with advanced disease and poor prognostic markers. Further investigation in larger cohorts with CK lacking HR-FISH is needed to elucidate which mechanisms underlie the poor outcome of this subgrou