JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms.

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

JAK2, CALR, and MPL Mutation Profiles in Colombian patients with BCR-ABL Negative Myeloproliferative Neoplasms

Background: Among the chronic myeloproliferative neoplasms (MPNs) not associated with BCR-ABL mutations are polycythemia vera, primary myelofibrosis, and essential thrombocythemia. These diseases are caused by mutations in genes, such as the JAK2, MPL, and CALR genes, which participate in regulating the JAK-STAT signaling pathway. Objective: This study aimed to establish the frequencies of mutations in the JAK2, MPL, and CALR genes in a group of Colombian patients with a negative clinical diagnosis of BCR-ABL chronic myeloproliferative neoplasms. Methods: The JAK2 V617F and MPL W515K mutations and deletions or insertions in exon 9 of the CALR gene were analyzed in 52 Colombian patients with polycythemia vera, primary myelofibrosis, and essential thrombocythemia. Results: The JAK2V617F mutation was carried by 51.9% of the patients, the CALR mutation by 23%, and the MPL mutation by 3.8%; 23% were triple-negative for the mutations analyzed. In these neoplasms, 6 mutation types in CALR were identified, one of which has not been previously reported. Additionally, one patient presented a double mutation in both the CALR and JAK2 genes. Regarding the hematological results for the mutations, significant differences were found in the hemoglobin level, hematocrit level, and platelet count among the three neoplasms. Conclusion: Thus, this study demonstrates the importance of the molecular characterization of the JAK2, CALR and MPL mutations in Colombian patients (the genetic context of which remains unclear in the abovementioned neoplasms) to achieve an accurate diagnosis, a good prognosis, adequate management, and patient survival.

Antecedentes: Entre las neoplasias mieloproliferativas crónicas no asociadas con mutaciones BCR-ABL se encuentran la policitemia vera, la mielofibrosis primaria y la trombocitemia esencial. Estas enfermedades están causadas por mutaciones en genes, como los genes JAK2, MPL y CALR, que participan en la regulación de la vía de señalización JAK-STAT. Objetivo: Establecer las frecuencias de mutaciones en los genes JAK2, MPL y CALR en un grupo de pacientes colombianos con diagnóstico clínico negativo de NMP BCR-ABL. Metodos: Se analizaron las mutaciones y deleciones o inserciones JAK2 V617F y MPL W515K en el exón 9 del gen CALR en 52 pacientes colombianos con policitemia vera, mielofibrosis primaria y trombocitemia esencial. Resultados: La mutación JAK2V617F la portaban el 51.9% de los pacientes, la mutación CALR el 23.0% y la mutación MPL el 3.8%; El 23.0% fueron triple negativos para las mutaciones analizadas. En estas neoplasias se identificaron seis tipos de mutación en CALR, uno de los cuales no ha sido reportado previamente. Además, un paciente presentó una doble mutación tanto en el gen CALR como en el JAK2. En cuanto a los resultados hematológicos para las mutaciones, se encontraron diferencias significativas en el nivel de hemoglobina, el nivel de hematocrito y el recuento de plaquetas entre las tres neoplasias. Conclusiones: Así, este estudio demuestra la importancia de la caracterización molecular de las mutaciones JAK2, CALR y MPL en pacientes colombianos (cuyo contexto genético aún no está claro en las neoplasias antes mencionadas) para lograr un diagnóstico certero, un buen pronóstico, un manejo adecuado y una mejoría del paciente. supervivencia.

Leucemia linfocítica crónica y deleción del gen TP53: reporte de un caso y revisión de la literatura / Chronic lymphocytic Leukemia and deletion of the TP53 gene: Case report and literature review

RESUMEN Las alteraciones genéticas en el gen TP53 están presentes entre el 5 al 8 % de los pacientes de leucemia linfocítica crónica (LLC) en el momento del diagnóstico. Estos casos se relacionan con un mal pronóstico debido a su resistencia al tratamiento estándar. Presentamos el caso de un paciente masculino de 52 años diagnosticado con LLC, expresión del marcador CD38 y una deleción en el gen TP53 (17p13.1). Tras la evaluación posterior del tratamiento, se observó enfermedad mínima residual lo que llevó a un trasplante haploidéntico de progenitores hematopoyéticos. Debido al alto riesgo de recaída, su edad y la ausencia de comorbilidades, era la única opción curativa hasta la fecha para la LLC. El objetivo de este trabajo es realizar una revisión de la literatura que sirva como base para analizar el caso clínico presentado, en el marco de las implicaciones clínicas, pronóstico y respuesta al tratamiento en los individuos con LLC que presentan alteraciones en el gen TP53.

SUMMARY Genetic alterations in the TP53 gene are present in 5 to 8% of chronic lymphocytic leukemia (CLL) cases at the time of diagnosis. These cases are typically associated with poor prognosis due to their resistance against standard CLL treatment. In our report a 52-yearold male patient was diagnosed with CLL, CD38 expression and a deletion in the TP53 gene (17p13.1). Upon evaluation post-treatment, minimal residual disease (MDR) was observed, and a haploidentical stem cell transplant was performed. Because of the high risk of relapse, his age, and the absence of comorbidities it was the only curative option to date for CLL. The purpose of this article is to complete a literature review that will give a basis to analyze the clinical case presented, within the framework of the clinical implications, prognosis, and response to treatment in patients with CLL who present with aberrations of the TP53 gene.

A non-coding RNASEH1 gene variant associates with type 1 diabetes and interacts with HLA tagSNPs in families from Colombia.

OBJECTIVES: RNASEH1 gene has recently been associated with type 1 diabetes (T1D) in Colombia. The purpose of this study was to fine mapping the putative functional variant in RNASEH1 and testing its interaction with HLA tagSNPs. METHODS: Two-hundred nuclear families with T1D were included in this study. Probands were tested for GAD65 and IA-2 autoantibodies. Genotyping was performed using 20 coding tagSNPs uncovered through Sanger sequencing (N = 96), in addition to 23 tagSNPs chosen from 1000genomes to cover the extent of the gene region. Also, 45 tagSNPs for classic HLA alleles associated with T1D were also genotyped. The transmission disequilibrium test (TDT) was used to test for association and a multiple testing correction was made using permutation. Interaction between RNASEH1 variants and HLA was evaluated by means of the M-TDT test. RESULTS: We identified 20 variants (15 were novel) in the 96 patients sequenced. None of these variants were in linkage disequilibrium. In total, 43 RNASEH1 variants were genotyped in the 200 families. Association between T1D and rs7607888 was identified (P = .002). Haplotype analysis involving rs7607888 variant revealed even stronger association with T1D (most significative P = .0003). HLA tagSNPs displayed stronger associations (OR = 6.39, 95% CI = 4.33-9.44, P-value = 9.74E-28). Finally, we found several statistically significant interactions of HLA variants with rs7607888 (P-value ranged from 8.77E-04 to 5.33E-12). CONCLUSION: Our results verify the association of rs7607888 in RNASEH1 gene with T1D. It is also shown in the interaction between RNASEH1 and HLA for conveying risk to T1D in Northwest Colombia. Work is underway aiming to identify the actual classic HLA alleles associated with the tagSNPs tested here.

Type 1 diabetes loci display a variety of native American and African ancestries in diseased individuals from Northwest Colombia.

BACKGROUND: Type 1 diabetes (T1D) is a complex disease with a higher incidence in Europeans than other populations. The Colombians Living in Medellin (CLM) is admixed with ancestry contributions from Europeans, Native Americans (NAT) and Africans (AFR). AIM: Our aim was to analyze the genetic admixture component at candidate T1D loci in Colombian individuals with the disease. METHODS: Seventy-four ancestry informative markers (AIMs), which tagged 41 T1D candidate loci/genes, were tested by studying a cohort of 200 Northwest Colombia diseased individuals. T1D status was classified by testing for glutamic acid decarboxylase (GAD-65 kDa) and protein tyrosine-like antigen-2 auto-antibodies in serum samples. Candidate loci/genes included HLA, INS, PTPN22, CTLA4, IL2RA, SUMO4, CLEC16A, IFIH1, EFR3B, IL7R, NRP1 and RNASEH1, amongst others. The 1,000 genome database was used to analyze data from 94 individuals corresponding to the reference CLM. As the data did not comply with a normal distribution, medians were compared between groups using the Mann-Whitney U-test. RESULTS: Both T1D patients and individuals from CLM displayed mainly European ancestry (61.58 vs 62.06) followed by Native American (27.34 vs 27.46) and to a lesser extent the AFR ancestry (10.28 vs 10.65) components. However, compared to CLM, ancestry of T1D patients displayed a decrease of NAT ancestry at gene EFR3B (24.30 vs 37.10) and an increase at genes IFIH1 (32.07 vs 14.99) and IL7R (52.18 vs 39.18). Also, for gene NRP1 (36.67 vs 0.003), we observed a non-AFR contribution (attributed to NAT). Autoimmune patients (positive for any of two auto-antibodies) displayed lower NAT ancestry than idiopathic patients at the MHC region (20.36 vs 31.88). Also, late onset patients presented with greater AFR ancestry than early onset patients at gene IL7R (19.96 vs 6.17). An association analysis showed that, even after adjusting for admixture, an association exists for at least seven such AIMs, with the strongest findings on chromosomes 5 and 10 (gene IL7R, P = 5.56 × 10-6 and gene NRP1, P = 8.70 × 10-19, respectively). CONCLUSION: Although Colombian T1D patients have globally presented with higher European admixture, specific T1D loci have displayed varying levels of Native American and AFR ancestries in diseased individuals.

Correlating the global increase in type 1 diabetes incidence across age groups with national economic prosperity: A systematic review.

BACKGROUND: The global epidemiology of type 1 diabetes (T1D) is not yet well known, as no precise data are available from many countries. T1D is, however, characterized by an important variation in incidences among countries and a dramatic increase of these incidences during the last decades, predominantly in younger children. In the United States and Europe, the increase has been associated with the gross domestic product (GDP) per capita. In our previous systematic review, geographical variation of incidence was correlated with socio-economic factors. AIM: To investigate variation in the incidence of T1D in age categories and search to what extent these variations correlated with the GDP per capita. METHODS: A systematic review was performed to retrieve information about the global incidence of T1D among those younger than 14 years of age. The study was carried out according to the PRISMA recommendations. For the analysis, the incidence was organized in the periods: 1975-1999 and 2000-2017. We searched the incidence of T1D in the age-groups 0-4, 5-9 and 10-14. We compared the incidences in countries for which information was available for the two periods. We obtained the GDP from the World Bank. We analysed the relationship between the incidence of T1D with the GDP in countries reporting data at the national level. RESULTS: We retrieved information for 84 out of 194 countries around the world. We found a wide geographic variation in the incidence of T1D and a worldwide increase during the two periods. The largest contribution to this increase was observed in the youngest group of children with T1D, with a relative increase of almost double when comparing the two periods (P value = 2.5 × e-5). Twenty-six countries had information on the incidence of T1D at the national level for the two periods. There was a positive correlation between GDP and the incidence of T1D in both periods (Spearman correlation = 0.52 from 1975-1999 and Spearman correlation = 0.53 from 2000-2017). CONCLUSION: The incidence increase was higher in the youngest group (0-4 years of age), and the highest incidences of T1D were found in wealthier countries.