Journal of the Association of Genetic Technologists最新文献

Objectives: Up to 90% of cases of chronic myeloid leukemia (CML) are myeloproliferative disorders characterized by a Philadelphia (Ph) chromosome with a classical t(9;22)(q34;q11). Of all CML patients, 5-10% show variant Philadelphia translocations (vPh) and are an area of research interest for their significance in predicting response to various therapies, including tyrosine kinase inhibitors. They are also being studied for prognosticating multi-year survival outcomes in varied patient populations, with conflicting results. We included 238 patients for conventional cytogenetic and fluorescence in situ hybridization study from January 2018 to October 2018. Patients with vPh in CML-Chronic Phase (CML-CP) were analyzed with respect to their demographic parameters, response to imatinib therapy, and survival. Out of 238 patients diagnosed with CML-CP, 8 patients (3.3%) showed vPh. The most common chromosomes involved in these translocations were 1, 2, 3, 4, 7, 11 and 12. In almost all the cases with variant Ph chromosome, the BCR-ABL rearrangement was detected by molecular methods or by fluorescence in situ hybridization (FISH). All patients were treated with imatinib as a first-line therapy. Rates of complete hematological response, complete cytogenetic response, and major molecular response were similar in all patients with classical Ph and variant Ph chromosome. Our data suggest that prognosis of CML patients with vPh in CML has no significant effect in predicting response to imatinib or in predicting survival.

Objectives: We present the case of an 83-year-old female with a long history of B-CLL followed by observation only. Twelve years after her diagnosis of CLL, routine follow-up chromosome analysis of peripheral blood revealed an abnormal metaphase with a dup(3)(q21q27) in 18 of 20 metaphase cells. To further characterize the abnormal chromosome 3, fluorescence in situ hybridization (FISH) was performed using the Abbott BCL6 probe for 3q27. An additional BCL6 signal was observed in 303 of the 500 interphase nuclei examined. The ISCN was reported as 46,XX,dup(3)(q21q27)[1]/46,XX[2]. nuc ish(5'BCL6, 3'BCL6)x3(5'BCL6 with 3'BCL6x3)[303/500]. This abnormality was seen again in one of three available metaphases in a follow-up peripheral blood study five years later, consistent with persistent disease. Molecular genetic analysis identified the presence of somatic hypermutation of the immunoglobulin heavy chain gene variable region (IGH-V), which is recognized as an independent favorable prognostic marker in CLL. FISH analysis was negative for loss of SEC63 (6q21), amplification of MYC (8q24), loss of ATM (11q22.3), trisomy 12, loss of D13S319 (13q14.3), loss of TP53 (17p13.1) and CCND1/MYEOV IGH rearrangement [t(11;14)(q13;q32.30)]. Partial trisomy 3 is a relatively rare event seen in B-CLL, with commonly overrepresented segments including the q21-23 region and the q25-29 region of the long arm of chromosome 3, as well as changes leading to gains of 3q26- q27. The clinical significance of this finding in B-CLL is uncertain; however, our patient remains well and has not required therapy 17 years after her initial diagnosis.

Objectives: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) accounts for ~15% of patients with high-risk ALL with an activated tyrosine kinase profile similar to Philadelphia chromosome positive ALL, without the presence of BCR-ABL1 rearrangement. ABL-class genes (ABL1, ABL2, PDGFRB, CSF1R and CRLF2) comprise the second major subgroup of Ph-like ALL cases but presence of ABL2 gene rearrangement in leukemia is rarely reported. We report a novel case of ABL2 chromosomal rearrangement that results from t(1;7)(q25;q32) in a patient with high-risk ALL.

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.