Journal of the Association of Genetic Technologists最新文献

Objectives: Precursor B-cell acute lymphoblastic leukemia (B-ALL) is one of the most common neoplasms. It is characterized by genetic and epigenetic aberrations. The most remarkable mechanisms involved in epigenetic abnormalities are DNA methylation and acetylation. Methylation of CpG islands in promoter regions and acetylation of lysine residues regulate gene expression. Several studies have shown that patients with B-ALL show aberrant DNA methylation in a genome-wide scale. Histone deacetylases (HDAC) regulate gene expression by removing acetyl groups from lysine residues and histone acetyltransferase (HAT) adds acetyl groups. A hematologic malignancy like B-ALL may be very sensitive to small-molecule inhibitors that target these epigenetic mechanisms and therefore may induce expression of pro-apoptotic factors. Thus, HDAC inhibitors (HDACi), DNA methyltransferase inhibitors (DNMTi) and histone acetyltransferase inhibitors (HATi) have been developed as therapies. The objective of this review is to summarize the different epigenetic mechanisms involved in B-ALL.

Objectives: Turner syndrome was first described to encompass a shared set of physical features displayed by a subset of female patients including short stature and lack of sexual development. Half of cases are due to complete loss of an X chromosome, while the remainder are due to other alterations of the X chromosome that disrupt genes necessary for normal physical and sexual development. The SHOX gene, located at Xp22.33, is essential for the growth and maturation of bone, while genes on Xq are important for ovarian function. Thus, loss of an X chromosome results in phenotypic short stature and amenorrhea typically seen in Turner syndrome. We present a unique case of Turner syndrome in a 16-year-old girl with primary amenorrhea and above-average height, in which karyotype revealed a derivative X chromosome resulting in partial Xp trisomy and partial Xq monosomy [46,X,der(X)(pter->q21.2::p11.23->pter)]. We hypothesize this unique karyotype explains the atypical phenotypic presentation of this patient.

Objectives: Acute T-lymphoblastic leukemia (T-ALL) is a malignancy of immature T-cells in children and adults and although it occurs less frequently than B-ALL, it carries a worse prognosis, especially after relapse. Molecular characterization and subtyping of T-ALL has begun to reveal vital insights into the complex biology of T-ALL and has prognostic and therapeutic implications. We present a case of a 19-year-old male who was found to have an early cortical phenotype T-ALL with multiple cytogenetic and somatic mutations including t(10;14) TLX-1 translocation, 9p22 CDKN2A deletion and missense mutations in PHF6, NOTCH-1, and FBXW7. Characterization of the significance of these mutations reveals that PHF6 mutations occur more frequently in adult males in association with TLX-1 translocations and early cortical phenotypes with NOTCH-1 activating mutations. We show mechanistically that these alterations occur in concert with one another to drive cell growth, cell survival and cell cycle progression. While still in development, further characterization of T-ALL is essential to provide more prognostic and therapeutically useful information.

Objectives: Disorders of sex development (DSD) include a group of conditions in which genotypes do not correlate with the typical male and female phenotypes. Numerical and structural abnormalities involving both autosomes and sex chromosomes have been observed in DSD. Specifically, deletions, duplications, and translocations involving specific genes as well as point mutations and less common aberrations have been implicated in the pathogenesis of these conditions. Finally, recent advances in analytical tools, namely chromosomal microarrays and sequencing methods, have greatly enhanced the precision with which DSD are genetically characterized and phenotypically correlated. Herein we report a case of a 24-year-old female patient who presented with secondary amenorrhea. Cytogenetic studies of her peripheral blood showed an abnormal clone with 45,X in three cells and the other was initially observed by chromosome analysis as 46,X,+mar in 27 cells. Molecular cytogenetics were performed to characterize the marker chromosome that showed two copies of the SRY, two copies of the heterochromatin Yq12, and two copies of the Y centromere Yp11.1-q11.1 on the marker chromosome, resulting in the identification of an isodicentric Y chromosome. Females with a 46,XY karyotype have gonadal dysgenesis and typically present as mosaic, along with a 45,X cell line. Some show small deletions of the short arm of the Y chromosome. Further studies based on the clinical picture, as well as possible prophylactic gonadectomy due to an increased risk of gonadal malignancy, gonadoblastoma or dysgerminoma, are suggested. Genetic counseling was recommended.

Objectives: Double-hit lymphomas represent 5% of cases of diffuse large B-cell lymphomas (DLBCL). They are currently recognized as highgrade B-cell lymphomas (HGBCL) with rearrangements of MYC and BCL2 and/or BCL6 by the 2016 WHO classification. One of these rearrangements is the translocation of the BCL2 gene (18q21.33), which codes for an apoptotic inhibitor, to the immunoglobulin heavy chain gene (14q32). In rarer instances, a translocation of the BCL2 gene to the immunoglobulin light chain gene on 2p11 also occurs. Both of these rearrangements result in consistent expression of the BCL2 protein. Another rearrangement is the translocation of the MYC proto-oncogene (8q24.21) to the IGH gene (14q32), which results in the overactivation of MYC. A t(14;18) can drive a low-grade malignant lymphoma, which is commonly a follicular or DLBCL. However, the presence of a t(8;14) abnormality may result in a highgrade malignant lymphoma, such as Burkitt's lymphoma. Both translocations affecting MYC and BCL2 rarely occur in an identical cell, and this lymphoid malignancy is known as BCL2 and MYC double-hit lymphoma. The incidence of aggressive B-cell lymphomas other than Burkitt's with a MYC breakpoint is difficult to assess, mainly because the published cytogenetics data may be biased toward specific categories of lymphomas and not consider the BCL2 involvement. BCL6/MYC double-hit lymphomas are less common, and most of these cases represent triple-hit lymphomas with involvement of BCL2 as well. In this review, we summarize and discuss the significance of cytogenetic abnormalities found in HGBCL and discuss possible directions for future research. We present two patients with double-hit lymphomas as well as our molecular cytogenetic approach to check the presence of MYC and BCL6 rearrangements as well as a BCL2/ IGH fusion.

Objectives: Soft tissue pathology encompasses a diverse range of benign and malignant soft tissue tumors. Definitive diagnosis is challenging due to the vast number of histologic subtypes (>100) and the potential for overlapping clinical, radiographic, histologic, and/or immunohistochemical features. Many institutions have moved away from cytogenetic analysis in the workup of soft tissue tumors; however, specific non-random cytogenetic abnormalities are characteristic of various tumor types and can reveal or confirm the diagnosis in challenging cases. We present a diagnostically challenging case of myxoid liposarcoma initially considered to be reactive in nature and only correctly diagnosed when karyotype analysis revealed the characteristic t(12;16)(q13;p11.2), thus altering patient care and management.

Objectives: While the complete form of trisomy 22 is seemingly incompatible with life, the mosaic form is a rare syndrome associated with developmental delays, intellectual disability, and dysmorphic features. Due in part to the difficulty of analyzing chromosomal mosaicism, many instances either go undiagnosed or have their diagnosis delayed. We report a case of mosaic trisomy 22 in a diamnionic-dichorionic twin with marked growth discordance and intra-uterine growth restriction, diagnosed in a 2-year-old with developmental delays, sensorineural hearing loss, cardiac and gastrointestinal abnormalities, and osteopenia of prematurity. Evaluation with a chromosomal oligonucleotide microarray with SNP analysis did not detect any copy number variants. Fibroblast metaphase karyotype analysis from a skin biopsy, however, showed trisomy 22 which was confirmed by FISH. Follow-up peripheral blood karyotype analysis and FISH studies revealed a normal male karyotype. This case highlights an instance where classical cytogenetics from two separate tissue types can provide a diagnosis that is more cost-effective than microarray analysis in assessing pediatric developmental delay. Trisomy 22 is the second most common aneuploidy in spontaneous miscarriages and has a nondescript and variable phenotype, especially in cases of mosaicism. As such, this condition may be underdiagnosed using the current recommended testing algorithm. Chromosomal microarray is considered first tier testing in an unrecognized phenotype with whole exome or whole genome sequencing, often performed on peripheral blood, as second tier testing. Diagnoses such as mosaic trisomy 22 suggest the second tier of testing in undiagnosed cases should also include a recommendation to look at alternative tissue types.

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.