Journal of the Association of Genetic Technologists最新文献

Objectives: Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) primarily characterized by increased red blood cell production. We report a case of a 68-year-old male with a history of PV. About four years later, the patient developed myelofibrosis. A bone marrow biopsy confirmed the presence of myelofibrosis confirmed by a hypercellular bone marrow (80%) with increased reticulin fibrosis (MF2-3), 5% blasts, and a normal 46,XY karyotype. A follow-up bone marrow biopsy documented acute myeloid leukemia (post-polycythemic myelofibrosis with acute leukemic transformation) with 20-30% blasts in the bone marrow. Chromosome analysis revealed an abnormal male karyotype with a t(3;8)(q26.2;q23) involving MECOM (EVI1) on 11q23 and confirmed by FISH and no PVTI rearrangement. To the best of our knowledge, this translocation has not been reported in acute myeloid leukemia (AML), de novo or therapy related-myelodysplastic syndrome (MDS), or MDS or myeloproliferative disorder progressing to AML. However, further studies need to be conducted to elucidate and identify the roles of genes other than MECOM involved in this peculiar translocation with such a poor prognosis.

Objectives: Chronic lymphocytic leukemia (CLL) is the most common type of hematological cancer diagnosed in human adults; however, it has been linked with a series of chromosomal abnormalities, the most common being deletion of 13q14. This chromosomal alteration leads to the deletion of the miR-15/16 cluster, as well as downregulation of DLEU7. Deletion of miR-15a and miR-16-1 causes overexpression of BCL2, an apoptosis suppressing protein, while the deletion of DLEU7 activates the NF-kB pathway. Both lead to the development of a pro-proliferative phenotype, an inhibition of apoptosis and prolonged cell life. This is the basis of the pathogenesis of indolent CLL where these pathways present themselves as essential targets for pharmacological therapy. Since BCL2 is, arguably, the most important factor in the pathogenesis of CLL, BCL2 inhibitors are beginning to acquire more relevance regarding targeted therapies for patients with CLL. Here we review the role of miR-15a and miR-16-1 in the pathogenesis of chronic lymphocytic leukemia, and the importance of microRNAs in targeted therapies.

Objectives: The GATA family of DNA binding proteins consists of six different transcription factors (GATA1-6), each with a diverse biologic function. The transcription factors GATA1-3 function primarily to orchestrate hematopoiesis; however, they have roles in non-hematopoietic cells as well. Much of our current knowledge of the GATA transcription factors has come through observation of disease states with known GATA mutations. The GATA2 protein has been shown to be vital for proliferation and maintenance of hematopoietic stem cells; mutations result in variable phenotypes including myelodysplastic syndrome. We present a case of a 19-year-old male with a history of pancytopenia and hypocellular bone marrow with dysplastic morphologic changes who underwent an extensive workup to determine an etiology. Molecular testing identified a germline GATA2 c.1081 C>T heterozygous mutation, allowing his case to be classified as the World Health Organization (WHO) entity: myeloid neoplasm with germline GATA2 mutation.

Objectives: Testicular germ cell tumors (TGCT) are a rare neoplasia but are still the most common malignancy in males between the ages of 15 and 44. TGCTs can be divided into two main types: Seminomas (SE) and non-seminomas (NS), the latter with an earlier age of onset and a worst prognosis. One of the most consistent features of TGCTs is the gain of material in the short arm of chromosome 12, that occurs in almost 100% of TGCT cases; 80% of them involve the formation of an isochromosome of the short arm i(12p). This might be the key step that allows the lesion to progress from a germ cell neoplasia in situ (GCNIS), which is a microscopic finding preceding the TGCT and without gain in 12p, to a TGCT. Some tumors, specially SE, present a more restricted amplification of certain 12p regions such as the 12p11.2-12.1 amplicon instead of the i(12p). The mechanism that associates the gain of 12p and the development of invasiveness is not yet well understood but it is believed a number of genes are involved, including DPPA3/STELLA, SOX5, PHC2, ATF7IP and proto-oncogenes Cyclin D2 and KRAS. Genome wide association studies have allowed us to acquire a better knowledge of the pathogenesis of this type of tumor, in which multiple genes show an increase in copy numbers, higher expression or activating mutations in genes related to the KIT/ KITLG pathway like KRAS, BRAF or KIT and KITLG itself. A less frequent subtype of TGCT found in older patients are spermatocytic tumors (ST). It does not develop from a GCNIS and presents a gain of genetic material in chromosome 9 instead of 12. It is believed the overexpression of the gene DMRT1, at 9p24.2, might have a role in the development of ST. In this review we are trying to delineate the most important loci involved in testicular germ tumors, the genes involved in this pathogenesis, and attempting to describe the possible mechanisms behind this tumorigenesis.

Objectives: Lipoblastomas are benign tumors composed of fat cells of varying degrees of maturation, from lipoblasts to mature adipocytes. These tumors typically affect young children under the age of three. Upregulation of the pleomorphic adenoma gene 1 (PLAG1), located on 8q12.1, is the primary driving force for lipoblastoma development. The most common mechanisms for PLAG1 upregulation are rearrangements of 8q11-13 and polysomy 8. We present a unique case of lipoblastoma in a three-year-old boy with a ring chromosome 8. To the best of our knowledge, this cytogenetic finding has only been described three times in the literature. We present this case to further document this rare cytogenetic abnormality in lipoblastomas and hypothesize that the formation of a ring 8 chromosome results in a promoter swapping event.

Variant databases serve as a resource for clinical molecular genetics laboratories. There is evidence of widespread interpretive and syntactic errors within the entries of both small and large-scale variant databases used for germline clinical molecular genetic interpretation reports. The over-dependence on variant databases for variant annotation, classification and reporting may be a potential source of error to clinical molecular genetics laboratories. Recent evidence suggests 12-50% of clinical test reports are in significant conflict with clinical reports from other laboratories. A non-systematic literature review of evidence of discrepancies within frequently used genetic variant databases used for generating clinical genetic tests is provided. The implications of and recommendations for addressing variant annotation, classification and interpretive errors are discussed.

DMD is a muscle-wasting disease. It is caused by mutations in the dystrophin gene which is found on the X chromosome. It has an X-linked recessive inheritance pattern and is passed on by the mother (carrier). It is a progressive disease that usually causes death in early adulthood-often in the 20s, although there have been improvements in treatment, so some patients make it into their 30s and occasionally 40s. In addition to the muscle wasting aspects, serious complications include heart or respiratory-related problems. It mostly affects boys, about 1 in every 3,500 or 5,000 male children. On September 19, 2016, the FDA approved Sarepta Therapeutics (SRPT)'s eteplirsen, which now goes by the trade name Exondys 51, to treat DMD. It is the first drug to be approved to treat the underlying causes of the disease. [http://www.biospace.com/News/victory-at-last-sarepta-stock-doublesas-the-fda/432777].

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is the most common hematological malignancy in children, and the t(12;21)(p13;q22) occurs in approximately 25% of these cases, making it is the most prevalent chromosomal abnormality. The t(12;21) which disrupts hematopoietic differentiation and proliferation, and can be present as a sole abnormality or within the context of a complex karyotype characterized by three or more chromosomal abnormalities. The prognosis of t(12;21) within a complex karyotype is extensively debated. In this review, we discuss the literature regarding t(12;21) and summarize the cytogenetic features found in 363 pediatric cases compiled from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. Cytogenetically, most of the cases had secondary chromosomal abnormalities, about half of which were in the context of a complex karyotype. Trisomy 21 was found to be the most common numerical abnormality in almost one-fifth of the cases, and deletions on chromosome 12 and 6 occurred in 16.9% and 12.5% of cases, respectively. In general, t(12;21) in B-ALL is associated with a favorable prognosis. Herein, we found no significant difference in survival outcome of t(12;21) with a on-complex or complex karyotype.

Chromosomal translocations involving the short arm of chromosome 2 (p13-25) and the distal part of the long arm of chromosome 3 (q25-29) are rare and still poorly studied to date. These abnormalities are common in myeloid neoplasms and are associated with a poor prognosis. Chromosomal abnormalities within the involved range of bands may contribute to the ectopic expression or formation of fusion genes involving the EVI1 gene, but the exact mechanism by which EVI1 affects leukemogenesis remains unclear. Herein, we report an analysis of 60 patient cases presenting various myeloid malignancies with t(2;3)(p13-25;q25-29) compiled from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer. In these studies, this translocation has been reported as a sole abnormality or within the context of a complex karyotype. Among the analysis in which molecular cytogenetic analysis was performed in order to assess the involvement of the EVI1 (ecotropic virus integration site 1 proton homolog) locus (n=19), 16 (84%) confirmed its rearrangement. In 37% of studies, the t(2;3) was seen as a sole abnormality (n=22). The t(2;3) was secondary in 11% of cases (n=4), and in 63% of the cases the t(2;3) had additional chromosomal abnormalities (n=38). Monosomy 7, deletion of the 5q arm, and translocations involving (9;22) were most common abnormalities in order of prevalence, occurring in 29% (n=11), 26% (n=10), and 13% (n=5) of case studies, respectively. These observations in the results of the literature on t(2;3), an anomaly not otherwise molecularly characterized, adds to the discussion of this translocation's approximate incidence in myeloid disease, and specifically in acute myeloid leukemia (AML). The data highlights its nonrandom nature and suggests that it is a part of the myeloid spectrum of disorders. Considering the severe clinical outcome associated with this translocation, this data provides information about a cytogenetic biomarker as well as an understanding of the significance of this set of chromosomal anomalies in the development of myeloid disease.

Erratum: Figure 1 on the last edition The Journal of the Association of Genetic Technologists. 2017;43(3): 113-127 does not contain the derivative 21. We are replacing this figure with the present one. In the section Secondary genetic aberrations we would like to add that: Deletions of 11q23 are observed in 5-6% of cases (Raynaud et al., 1999; Attarbaschi et al., 2004; Alvarez et al., 2005; Forestier et al., 2007).