New insights in the cytogenetic practice: Karyotypic chaos, non-clonal chromosomal alterations and chromosomal instability in human cancer and therapy response

Recently, non-clonal chromosomal alterations previously unappreciated are being proposed to be included in cytogenetic practice. The aim of this inclusion is to obtain a greater understanding of chromosomal instability (CIN) and tumor heterogeneity and their role in cancer evolution and therapy response. Although several genetic assays have allowed the evaluation of the variation in a population of cancer cells, these assays do not provide information at the level of individual cells, therefore limiting the information of the genomic diversity within tumors (heterogeneity). The karyotype is one of the few available cytogenetic techniques that allow us not only to identify the chromosomal alterations present within a single cell, but also allows us to profile both clonal (CCA) and non-clonal chromosomal alterations (NCCAs). A greater understanding of CIN and tumor heterogeneity in cancer could not only improve existing therapeutic regimens but could also be used as targets for the design of new therapeutic approaches. In this review we indicate the importance and significance of karyotypic chaos, NCCAs and CIN in the prognosis of human cancers. © 2017 by the authors. Licensee MDPI, Basel, Switzerland

Inhibición de la colinesterasa como biomarcador para la vigilancia de población ocupacionalmente expuesta a plaguicidas organofosforados

Cholinesterases are a group of catalytic enzymes whose activity can be diminished by different factors, including organophosphate pesticide exposure. These pesticides are reported as the most used in crop production worldwide, and therefore, those persons who are exposed through their work to these substances are at high risk of suffering adverse health effects. The aim of this review is to describe the use of the cholinesterase enzyme activity as biomarkers to monitor the health status of workers exposed to organophosphate pesticides. Scientific articles were consulted in seven online databases published between 2003 and 2019 using as descriptors: organophosphate poisoning, cholinesterase activity as a biomarker, and determination of cholinesterase in farmers. In this review, different studies that show the validity and usefulness of the use of cholinesterase activity as biomarkers to monitor populations occupationally exposed to organophosphate pesticides were referred. Occupational surveillance following the recommendations of the guidelines that prevent pesticide poisonings is more easily carried out by agricultural workers of companies compared to informal and independent farmers. Studies show that there are populations that have begun to give greater importance to monitoring the negative effects of organophosphates on the health of exposed workers using cholinesterase as biological biomarkers. Its utility improves when comparisons are made with pre-existing values and in unexposed persons.Las colinesterasas son un grupo de enzimas catalíticas, cuya actividad puede verse disminuida por diferentes factores, entre ellos la exposición a plaguicidas organofosforados. Mundialmente se reportan estos plaguicidas como los más utilizados en la producción de cultivos y, por lo tanto, quienes se exponen a través de sus labores a estas sustancias están en alto riesgo de sufrir efectos negativos sobre su salud. El objetivo de esta revisión es describir el uso de la actividad de las enzimas colinesterasas como biomarcadores para vigilar el estado de salud de los trabajadores expuestos a plaguicidas organofosforados. Se consultaron artículos científicos en siete bases de datos en línea, publicados entre el 2003 y el 2019, utilizando los siguientes descriptores: intoxicación por organofosforados, actividad de colinesterasas como biomarcador y determinación de colinesterasa en agricultores. En esta revisión fueron referidos diferentes estudios que dan cuenta de la validez y utilidad del uso de la actividad de colinesterasas como biomarcadores para monitorear poblaciones ocupacionalmente expuestas a plaguicidas organofosforados. La vigilancia ocupacional por medio de las recomendaciones de las guías que previenen las intoxicaciones por plaguicidas se realiza con mayor facilidad en trabajadores agrícolas de empresas que en agricultores informales e independientes. Los estudios demuestran que existen poblaciones que han empezado a darle mayor importancia al seguimiento de los efectos negativos de los organofosforados en la salud de trabajadores expuestos que emplean las colinesterasas como biomarcadores biológicos. Su utilidad mejora cuando se realizan comparaciones con valores preexistentes y en personas sin exposición

Ovarian Reserve Markers: An Update

Ovarian reserve (OR) is defined as the pool of follicles available to provide eggs cells throughout the fertile age in each woman and define the potential of fertility to predict the reproductive lifespan of women. Several studies have focused on the clinical use in order to identify women with a decreased ovarian function and to improve the clinical approach to these patients. In this chapter we will describe different OR markers such as antimullerian hormone (AMH) and follicle stimulating hormone (FSH), count by ultrasound of antral follicles (AFC) and ovarian volume. The measure of OR markers has been reported as an effective test to predict a possible failure of reproductive capacity and important tool in the primary prevention of infertility and other related problems. Therefore, we will show the clinical use of these markers in both healthy and infertile women studies. Additionally, we describe the most recent and promising progress in the OR evaluation by construction of algorithms

Integrated Genomic Analysis of Chromosomal Alterations and Mutations in B-Cell Acute Lymphoblastic Leukemia Reveals Distinct Genetic Profiles at Relapse

The clonal basis of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is complex and not fully understood. Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 BCP-ALL patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of the BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (p = 0.019). MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. TP53 was the most frequently mutated gene at relapse. Two TP53 mutations were detected only at relapse, whereas the three others showed an increase in their mutational burden at relapse. Clonal evolution patterns were heterogeneous, involving the acquisition, loss and maintenance of lesions at relapse. Therefore, this study provides additional evidence that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. Integrative NGS, aCGH and MLPA analysis enables better molecular characterization of the genetic profile in BCP-ALL patients during the evolution from diagnosis to relapse

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

[EN]Background: In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols. Methods: Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR). Results: A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036). Conclusions: TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.European Commision (EC). Funding FP7/SP1/HEALTH. Project Code: 30624

Genome-wide DNA copy number analysis of acute lymphoblastic leukemia identifies new genetic markers associated with clinical outcome

Altres ajuts: FUCALHH 2013; HUS272U13; GRS 994/A/14, BIO/SA10/14, BIO/SA31/13; Fundación Española de Hematología y Hemoterapia (FEHH), Universidad Pedagógica y Tecnológica de Colombia 223-2011Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge. Aims: To characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL

New Insights in the Cytogenetic Practice: Karyotypic Chaos, Non-Clonal Chromosomal Alterations and Chromosomal Instability in Human Cancer and Therapy Response

Recently, non-clonal chromosomal alterations previously unappreciated are being proposed to be included in cytogenetic practice. The aim of this inclusion is to obtain a greater understanding of chromosomal instability (CIN) and tumor heterogeneity and their role in cancer evolution and therapy response. Although several genetic assays have allowed the evaluation of the variation in a population of cancer cells, these assays do not provide information at the level of individual cells, therefore limiting the information of the genomic diversity within tumors (heterogeneity). The karyotype is one of the few available cytogenetic techniques that allow us not only to identify the chromosomal alterations present within a single cell, but also allows us to profile both clonal (CCA) and non-clonal chromosomal alterations (NCCAs). A greater understanding of CIN and tumor heterogeneity in cancer could not only improve existing therapeutic regimens but could also be used as targets for the design of new therapeutic approaches. In this review we indicate the importance and significance of karyotypic chaos, NCCAs and CIN in the prognosis of human cancers

Microdelección 22q11.2: Aspectos genéticos y clínicos

Spa: La microdeleción 22q11.2 es un síndrome genético que provoca una serie de anormalidades congénitas que afecta múltiples sistemas y órganos, denominado síndrome de deleción 22q11.2 (22q11.2DS). Dicho síndrome está asociado con la perdida de ADN en el brazo largo del cromosoma 22. Es uno de los síndromes más prevalentes en los seres humanos afectando gravemente la calidad de vida de los pacientes. El objetivo es describirlas generalidades del síndrome de deleción 22q11.2, junto con sus características clínicas,y sus aspectos genéticos y moleculares. Se realizó una revisión en bases de datos científicas compilando artículos sobre la microdeleción 22q11.2 entre los años 2009 a 2016.El síndrome de deleción 22q11.2 es un síndrome sub-diagnosticado, el cual provoca un fenotipo altamente variable afectando potencialmente la calidad de vida del paciente. Se puede clasificar según el tamaño y la ubicación de la microdeleción; según su tamaño se clasifica en deleciones de tipo I, II y II, y de acuerdo a su ubicación las deleciones pueden ser proximales, centrales y distales