Journal of the Association of Genetic Technologists最新文献

Objectives: We report a 63-year-old male whose bone marrow morphology and flow cytometry showed evidence of B-Chronic Lymphocytic Leukemia (B-CLL). Chromosome analysis of the bone marrow showed an abnormal karyotype, described as 46,XY,t(18;22)(q21;q11.2)[19]/46,XY[1]. FISH analysis on interphase nuclei revealed an abnormal clone with loss of D13S319 (13q14.3) in 68.0% of the cells examined. Deletion of chromosome 13 is the most common cytogenetic abnormality identified in CLL (approximately 50% of CLL). Recent studies suggest that deletion of chromosome 13q14 in 65% or more nuclei by FISH is associated with an intermediate to unfavorable prognosis in CLL. The t(18;22)(q21;q11.2) present in this case, as well as the t(2;18)(p12;q21), are variants of the t(14;18)(q32;q21); all three are abnormalities in CLL. These abnormalities are found in less than 4% of CLL cases. They are usually present within the context of a complex karyotype in a subset of CLL, but can also be observed in cases of benign lymphocytosis. Herein, we report a t(18;22)(q21;q11.2) in a CLL patient as a sole cytogenetic abnormality by conventional cytogenetics, and with loss of 13q14.3, as determined by FISH. To the best of our knowledge, this is one of the few cases of its kind.

Objectives: Renal cell carcinoma (RCC) is a malignancy commonly encountered by both clinicians and pathologists. Different RCC subtypes are classified based on histologic features, immunohistochemistry profiles, and cytogenetic abnormalities. Accurate diagnosis of subtypes is important as it has prognostic and therapeutic implications. The most common RCC subtype is clear cell renal cell carcinoma (CCRCC); the most frequent genetic abnormalities associated with CCRCC are a deletion of the short arm of chromosome 3 involving 3p21 and mutations involving the Von Hippel-Lindau (VHL) gene. Advances in molecular pathology have identified additional molecular pathways leading to CCRCC. Researchers identified mutations of TCEB-1, monosomy 8, intact chromosome 3 and lack of VHL gene mutations in 4.7% of CCRCC. Additional evidence has been found recognizing RCC with monosomy 8 as a unique RCC subtype by describing cases with similar genetic profiles, non-specific immunohistochemistry, and histomorphology that overlapped with other known RCC types. At the University of Vermont Medical Center (UVMMC), conventional cytogenetics are obtained on all renal neoplasms. Three recent cases of RCC with monosomy 8, normal chromosome 3 morphology, clear cell cytology and non-specific immunohistochemistry profiles were identified. We present these cases to further document this unique subtype and highlight the importance of conventional cytogenetics in the diagnosis of renal cell carcinoma.

Objectives: We report here a 74-year-old male who was seen for recurrent respiratory infections, fatigue, and weight loss in November 2016. Bone marrow biopsy showed 90% involvement by plasma cell myeloma (PCM) [90% plasma cells, 40% cellular bone marrow]. Cytogenetic analysis of the bone marrow showed a complex karyotype described as: 53,Y,add(X)(p22.1),del(1)(p13p22),+3,add(3)(p13),add(4)(p12),+6,del(6)(q13q25),t(8;22)(q24.1;q11.2),+9,+11,+15,+15,+21[7]/46,XY[13]. This particular pattern with deletion 1p, deletion 6q, and a t(8;22)(q24;q11.2) within the context of a complex karyotype is seen in PCM. Fluorescence in situ hybridization analysis on the CDC138 sample was positive for additional copies of CEP7 (centromere 7), CEP9 (centromere 9), CEP11 (centromere 11), and CEP15 (centromere 15), suggesting polysomy. FISH using the MYC Vysis break apart probe showed evidence of MYC rearrangement similar to the breakpoint site seen in Burkitt lymphoma with t(8;22)(q24;q11). FISH using the IGL break apart probe (Cytocell, Cambridge, UK) showed evidence of a 22q11.2 rearrangement. The signal pattern showed a residual green signal (BCR), a green signal on the derivative 8, and a red signal on the derivative 22, suggesting that the breakpoint at 22q11.2 in this patient was located downstream of the BCR region of the IGL gene. The variant Burkitt-type translocation, t(8;22)(q24;q11), is a very rare abnormality in PCM, and this case is one of only several reported to date. In these patients, MYC abnormalities appear late in the course of the disease and have an immature phenotype. A review of several cases in the literature suggests that this translocation leads the MYC gene under direct regulation of the enhancer of the partner gene, and in our case, the IGL or a nearby gene, thereby causing high level transcription of MYC. This abnormality is usually present within a complex karyotype and is associated with tumor progression and a poor prognosis.

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].