Evaluation of the association between the JAK2 46/1 haplotype and chronic myeloproliferative neoplasms in a Brazilian population
TL;DR: The JAK2 46/1 haplotype, represented in this study by the presence of the G allele, is an important predisposing factor in the oncogenetic development of these neoplasms in the studied population.
About: This article is published in Clinics.The article was published on 2013-01-01 and is currently open access. It has received 41 citations till now. The article focuses on the topics: Myeloproliferative neoplasm & Population.
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TL;DR: Three basic types of paternal effect are distinguished and key questions that can serve as a road map for research on the proximate basis and evolutionary implications of paternal effects are outlined.
Abstract: Maternal effects are now universally recognised as a form of nongenetic parental influence on offspring but, until recently, paternal effects were regarded as an anomaly. Although it is now clear that paternal effects are both widespread and important, their proximate basis and evolutionary consequences have received little attention and remain poorly understood. In particular, because many paternal effects are mediated by maternal responses such as differential allocation, the boundary between paternal and maternal effects is sometimes blurred. We distinguish here three basic types of paternal effect and clarify the role of maternal responses in these effects. We also outline key questions that can serve as a road map for research on the proximate basis and evolutionary implications of paternal effects.
175 citations
TL;DR: Existing evidence does not support ICSI in preference over in vitro fertilization (IVF) in the general non-male factor ART population; however, in couples with unexplained infertility, I CSI is associated with lower fertilization failure rates than IVF.
Abstract: Intracytoplasmic sperm injection (ICSI) has become the most commonly used method of fertilization in assisted reproductive technology. The primary reasons for its popularity stem from its effectiveness, the standardization of the procedure, which means that it can easily be incorporated into the routine practice of fertility centres worldwide, and the fact that it can be used to treat virtually all forms of infertility. ICSI is the clear method of choice for overcoming untreatable severe male factor infertility, but its (over)use in other male and non-male factor infertility scenarios is not evidence-based. Despite all efforts to increase ICSI efficacy and safety through the application of advanced sperm retrieval and cryopreservation techniques, as well as methods for selecting sperm with better chromatin integrity, the overall pregnancy rates from infertile men remain suboptimal. Treating the underlying male infertility factor before ICSI seems to be a promising way to improve ICSI outcomes, but data remain limited. Information regarding the health of ICSI offspring has accumulated over the past 25 years, and there are reasons for concern as risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile have been observed to be greater in infants born as a result of ICSI than in naturally conceived children. However, as subfertility probably influences the risk estimates, it remains to be determined to what extent the observed adverse outcomes are related to parental factors or associated with ICSI.
131 citations
TL;DR: It is proposed that careful assessment of spermatozoal parameters is essential to achieve embryo development and a healthy live birth and the need for more research and the development of standardized protocols to assess the role of sperm factors affecting embryo quality.
Abstract: Advancing maternal and paternal age leads to a decrease in fertility, and hence, many infertile couples opt for assisted reproductive technologies [ART] to achieve biological parenthood. One of the key determinants of achieving a live outcome of ART, embryo quality, depends on both the quality of the oocyte and sperm that have created the embryo. Several studies have explored the effect of oocyte parameters on embryo quality, but the effects of sperm quality on the embryo have not been comprehensively evaluated. In this review, we assess the effect of various genetic factors of paternal origin on the quality and development of the embryo. The effects of sperm aneuploidy, sperm chromatin structure, deoxyribonucleic acid [DNA] fragmentation, role of protamines and histones, sperm epigenetic profile, and Y chromosome microdeletions were explored and found to negatively affect embryo quality. We propose that careful assessment of spermatozoal parameters is essential to achieve embryo development and a healthy live birth. However, the heterogeneity in test results and the different approaches of assessing a single sperm parameter highlight the need for more research and the development of standardized protocols to assess the role of sperm factors affecting embryo quality.
86 citations
TL;DR: Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK 2V617f mutation burden across increasing severity of myeloplasm from no disease to primary myelofibrosis.
Abstract: Clinical significance of the JAK2V617F mutation in patients with a myeloproliferative neoplasm has been the target of intensive research in recent years. However, there is considerably uncertainty about prognosis in JAK2V617F positive individuals without overt signs of myeloproliferative disease. In this study, we tested the hypothesis that increased JAK2V617F somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation in the time period 2003-2008. Of these, 48 were available for re-examination in 2012. Level of JAK2V617F mutation burden was associated with myeloproliferative neoplasm progression rate, consistent with a biological continuum of increasing JAK2V617F mutation burden across increasing severity of myeloproliferative neoplasm from no disease (n=8 at re-examination) through essential thrombocythemia (n=20) and polycythemia vera (n=13) to primary myelofibrosis (n=7). Among those diagnosed with a myeloproliferative neoplasm only at re-examination in 2012, in the preceding years JAK2V617F mutation burden increased by 0.55% per year, erythrocyte volume fraction increased by 1.19% per year, and erythrocyte mean corpuscular volume increased by 1.25% per year, while there was no change in platelet count or erythropoietin levels. Furthermore, we established a JAK2V617F mutation burden cut-off point of 2% indicative of disease versus no disease; however, individuals with a mutation burden below 2% may suffer from a latent form of myeloproliferative disease revealed by a slightly larger spleen and/or slightly higher lactic acid dehydrogenase concentration compared to controls. Of all 63 JAK2V617F positive individuals, 48 were eventually diagnosed with a myeloproliferative neoplasm.
75 citations
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TL;DR: BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.
Abstract: Exposure to bisphenol A (BPA) has been related to male reproductive disorders. Since this endocrine disruptor also displays genotoxic and epigenotoxic effects, it likely alters the spermatogenesis, a process in which both hormones and chromatin remodeling play crucial roles. The hypothesis of this work is that BPA impairs early embryo development by modifying the spermatic genetic and epigenetic information. Zebrafish males were exposed to 100 and 2000 μg/L BPA during early spermatogenesis and during the whole process. Genotoxic and epigenotoxic effects on spermatozoa (comet assay and immunocytochemistry) as well as progeny development (mortality, DNA repairing activity, apoptosis and epigenetic profile) were evaluated. Exposure to 100 µg/L BPA during mitosis slightly increased sperm chromatin fragmentation, enhancing DNA repairing activity in embryos. The rest of treatments promoted high levels of sperm DNA damage, triggering apoptosis in early embryo and severely impairing survival. Regarding epigenetics, histone acetylation (H3K9Ac and H3K27Ac) was similarly enhanced in spermatozoa and embryos from males exposed to all the treatments. Therefore, BPA male exposure jeopardizes embryonic survival and development due to the transmission of a paternal damaged genome and of a hyper-acetylated histone profile, both alterations depending on the dose of the toxicant and the temporal window of exposure.
53 citations
References
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TL;DR: In this study of Brazilian patients, the JAK2 V617F mutation was detected in four out of 49 patients with PV, 14 out of 25 patients with IMF, and in eight out of 29 patients with ET, which is in accordance with previous screenings of this mutation in other populations.
Abstract: Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) are myeloproliferative disorders (MPD) that arise from the clonal proliferation of a pluripotent hematopoietic progenitor, leading to the overproduction of one or more myeloid lineages. Recently, a specific mutation in the JAK2 gene, which encodes a tyrosine kinase, has been shown to be associated with the myeloproliferative phenotype observed in PV, ET and IMF. In this study of Brazilian patients, the JAK2 V617F mutation [c.1887G > T) was detected in four out of 49 patients with PV (96%), 14 out of 25 patients with IMF (56%), and in eight out of 29 patients with ET, which is in accordance with previous screenings of this mutation in other populations.
11 citations
"Evaluation of the association betwe..." refers methods in this paper
...All of the blood samples obtained from the cMPN patients were genotyped for the JAK2 V617F mutation using a PCR-RFLP assay as previously described (14)....
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...Blood samples were also collected from 90 healthy individuals (blood donors from the Hemocentro Regional de Maringá) and used as controls, as the JAK2 V617F mutation is not found in healthy individuals (3-6,13,14)....
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TL;DR: A somatic mutation occurs primarily on one particular germline JAK2 haplotype, which may account for as much as 50% of the risk to first-degree relatives, which provides new directions for unraveling the pathogenesis of MPN.
Abstract: Myeloproliferative neoplasms (MPNs) are a group of closely related stem-cell-derived clonal proliferative diseases Most cases are sporadic but first-degree relatives of MPN patients have a five- to seven-fold increased risk for developing an MPN The tumors of most patients carry a mutation in the Janus kinase 2 gene (JAK2V617F) Recently, three groups have described a strong association of JAK2 germline polymorphisms with MPN in patients positive for JAK2V617F The somatic mutation occurs primarily on one particular germline JAK2 haplotype, which may account for as much as 50% of the risk to first-degree relatives This finding provides new directions for unraveling the pathogenesis of MPN
8 citations
"Evaluation of the association betwe..." refers background in this paper
...Another hypothesis suggests that the JAK2 46/1 haplotype could confer a proliferative or survival advantage to the neoplastic clone, which may explain the increased frequency of the JAK2 46/1 haplotype in different populations of cMPN patients (18)....
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...It was suggested that the JAK2 46/1 haplotype brings genetic instability to the JAK2 gene, favoring the emergence of JAK2 acquired mutations, such as the JAK2 V617F and JAK2 exon 12 mutations (10-12,18)....
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...As mentioned above, one hypothesis is that a genetic instability brought by the presence of a specific inherited haplotype facilitated the emergence of an acquired JAK2 mutation (10-12,18)....
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...Recent reports have suggested that hereditary genetic factors, specifically the JAK2 haplotypes, can strongly contribute to the development of cMPN (11,12,16-18)....
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TL;DR: In this article, the JAK2 V617F mutation and its relationship to the myeloproliferative phenotype and its implications in the clinical approach of patients are discussed.
Abstract: Myeloproliferative disorders are clonal hematopoietic diseases that are characterized by the amplification of one or more myeloid lineages. Polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis and chronic myeloid leukemia are considered classic myeloproliferative disorders and share common clinical and biological features. While the genetic basis of chronic myeloid leukemia is shown to be the constitutive active protein BCR-ABL, the main molecular lesions in polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis remain unknown. This review focuses on the recent discovery of the JAK2 V617F mutation, its relationship to the myeloproliferative phenotype and implications in the clinical approach of patients.
5 citations
TL;DR: Investigating the presence of mutations in the points most frequent for mutations (hotspot mutations) in phosphatidylinositol-3-kinase, Janus kinase 2, FMS-like tyrosine kinase 3, FLT3 and nucleophosmin genes shows that hotspot mutations in these genes are not common in MDS patients; nevertheless, JAK2 mutations may be present in myelodysplasia during disease progression.
5 citations
TL;DR: The discovery of the JAK2V617F mutation has been essential in understanding the genetic basis of chronic myeloproliferative neoplasms, providing some idea on how a single mutation can result in three different chronic myelin-rich neoplasm phenotypes.
Abstract: Chronic myeloproliferative neoplasms arise from clonal proliferation of hematopoietic stem cells. According to the World Health Organization myeloproliferative neoplasms are classified as: chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia, hypereosinophilic syndrome, mast cell disease, and unclassifiable myeloproliferative neoplasms. In the revised 2008 WHO diagnostic criteria for myeloproliferative neoplasms, mutation screening for JAK2V617F is considered a major criterion for polycythemia vera diagnosis and also for essential thrombocythemia and primary myelofibrosis, the presence of this mutation represents a clonal marker. There are currently two hypotheses explaining the role of the JAK2V617F mutation in chronic myeloproliferative neoplasms. According to these theories, the mutation plays either a primary or secondary role in disease development. The discovery of the JAK2V617F mutation has been essential in understanding the genetic basis of chronic myeloproliferative neoplasms, providing some idea on how a single mutation can result in three different chronic myeloproliferative neoplasm phenotypes. But there are still some issues to be clarified. Thus, studies are still needed to determine specific molecular markers for each subtype of chronic myeloproliferative neoplasm.
4 citations
"Evaluation of the association betwe..." refers background in this paper
...Consequently, JAK2 V617F mutation screening became a cornerstone in the molecular diagnostic approach for cMPN (1,7)....
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