1q jumping translocation as a biomarker in myeloid malignancy: frequently mutated genes associated with bad prognosis and low survival.

1q jumping translocation (JT) is rare and its molecular profiles in myeloid malignancies are not well-known. This study evaluated gene mutations in 1q-JT cohorts (0.38%) from hematological malignant specimens that underwent genetic analysis at the Johns Hopkins Hospital (n = 11,908) and the MD Anderson Cancer Center. 1q-JT had frequent mutations in eleven genes, most of which are associated with worse prognosis. BCOR mutations significantly co-occurred with others. Patients tended to have mutations in DNA-repair, spliceosome, and epigenetic modification pathways, though genes utilized within each of these pathways were not randomly distributed. Multi-, albeit overlapping, pathway interruptions tended to manifest in mutations of two gene sets. One gene set consisted of SF3B1 (spliceosome) and TET2 (epigenetic modification), while the other consisted of STAG2 (DNA repair), SRSF2, U2AF (spliceosome), ASXL1, KMT2D (epigenetic modification), BCOR, and GATA2 (transcription factors). An "intermediate" JT-like rearrangement may represent an early sign of occurring 1q-JT. Treatments (hypomethylating agents) and unique structures of the short arms of acrocentric chromosomes may contribute to 1q-JT formation in myeloid malignancies. The median overall survival after identification of a JT was 10 months (95% confidence interval, 5-15 months). Our cohort represents the largest number of myeloid malignancies from multi-centers with before and after the 1q-JT event analyzed to date. Overall, this study identified specific molecular profiles that are associated with 1q-JT in myeloid malignancies. 1q-JT could serve as a poor prognosis biomarker in myeloid malignancies, which could be important in making well-informed clinical decisions and treatment strategies.

Mosaicism for Robertsonian jumping translocation at amniocentesis: 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY, genetic counseling, prenatal diagnosis and postnatal follow-up in a pregnancy with a favorable fetal outcome.

OBJECTIVE: We present genetic counseling, prenatal diagnosis and postnatal follow-up of 45,XY,der(15;22)(q10;q10)mat/46,XY,i(15)(q10)/46,XY at amniocentesis in a pregnancy with a favorable fetal outcome. CASE REPORT: A 27-year-old, primigravid woman underwent amniocentesis at 19 weeks of gestation because increased nuchal translucency thickness, and the result was 45,XY,der(15;22)(q10;q10)[29]/46,XY,i(15)(q10)[3]/46,XY[5]. Simultaneous array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed arr (1-22) × 2, (X,Y) × 1. The maternal karyotype was 45,XX,der(15;22)(q10;q10), and the paternal karyotype was 46,XY. She was referred for genetic counseling, and repeat amniocentesis performed at 23 weeks of gestation revealed 45,XY,der(15;22)(q10;q10)mat[23]/45,XY,-22[2]. aCGH analysis on uncultured amniocytes detected no genomic imbalance, and polymorphic DNA marker analysis excluded uniparental disomy (UPD) 15. Fluorescence in situ hybridization (FISH) analysis using the chromosome 15q specific probe and the chromosome 22q specific probe detected three 15q signals in 4/104 cells (3.8%). The woman was advised to continue the pregnancy, and, a 3186-g phenotypically normal male baby was delivered at 38 weeks of gestation. The umbilical cord had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells). When follow-up at age seven months, the neonate was normal in development, the peripheral blood had a karyotype of 45,XY,der(15;22)(q10;q10) (40/40 cells), and the buccal mucosal cells had normal signals in all 100 cells. CONCLUSIONS: Mosaicism for Robertsonian jumping translocations at amniocentesis can be a transient condition and can be associated with a familial Robertsonian translocation and a favorable fetal outcome. Prenatal diagnosis of a Robertsonian jumping translocation involving chromosome 15 should include UPD 15 testing to exclude UPD 15.

Complex/cryptic EWSR1::FLI1/ERG Gene Fusions and 1q Jumping Translocation in Pediatric Ewing Sarcomas.

Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES.

Investigating the Function of Human Jumping Translocation Breakpoint Protein (hJTB) and Its Interacting Partners through In-Solution Proteomics of MCF7 Cells.

Human jumping translocation breakpoint (hJTB) gene is located on chromosome 1q21 and is involved in unbalanced translocation in many types of cancer. JTB protein is ubiquitously present in normal cells but it is found to be overexpressed or downregulated in various types of cancer cells, where this protein and its isoforms promote mitochondrial dysfunction, resistance to apoptosis, genomic instability, proliferation, invasion and metastasis. Hence, JTB could be a tumor biomarker for different types of cancer, such as breast cancer (BC), and could be used as a drug target for therapy. However, the functions of the protein or the pathways through which it increases cell proliferation and invasiveness of cancer cells are not well-known. Therefore, we aim to investigate the functions of JTB by using in-solution digestion-based cellular proteomics of control and upregulated and downregulated JTB protein in MCF7 breast cancer cell line, taking account that in-solution digestion-based proteomics experiments are complementary to the initial in-gel based ones. Proteomics analysis allows investigation of protein dysregulation patterns that indicate the function of the protein and its interacting partners, as well as the pathways and biological processes through which it functions. We concluded that JTB dysregulation increases the epithelial-mesenchymal transition (EMT) potential and cell proliferation, harnessing cytoskeleton organization, apical junctional complex, metabolic reprogramming, and cellular proteostasis. Deregulated JTB expression was found to be associated with several proteins involved in mitochondrial organization and function, oxidative stress (OS), apoptosis, and interferon alpha and gamma signaling. Consistent and complementary to our previous results emerged by using in-gel based proteomics of transfected MCF7 cells, JTB-related proteins that are overexpressed in this experiment suggest the development of a more aggressive phenotype and behavior for this luminal type A non-invasive/poor-invasive human BC cell line that does not usually migrate or invade compared with the highly metastatic MDA-MB-231 cells. This more aggressive phenotype of MCF7 cells related to JTB dysregulation and detected by both in-gel and in-solution proteomics could be promoted by synergistic upregulation of EMT, Mitotic spindle and Fatty acid metabolism pathways. However, in both JTB dysregulated conditions, several downregulated JTB-interacting proteins predominantly sustain antitumor activities, attenuating some of the aggressive phenotypical and behavioral traits promoted by the overexpressed JTB-related partners.

Investigation of the effects of downregulation of jumping translocation breakpoint (JTB) protein expression in MCF7 cells for potential use as a biomarker in breast cancer.

MCF7 is a commonly used luminal type A non-invasive/poor-invasive human breast cancer cell line that does not usually migrate or invade compared with MDA-MB-231 highly metastatic cells, which emphasize an invasive and migratory behavior. Under special conditions, MCF7 cells might acquire invasive features. The aberration in expression and biological functions of the jumping translocation breackpoint (JTB) protein is associated with malignant transformation of cells, based on mitochondrial dysfunction, inhibition of tumor suppressive function of TGF-ß, and involvement in cancer cell cycle. To investigate new putative functions of JTB by cellular proteomics, we analyzed the biological processes and pathways that are associated with the JTB protein downregulation. The results demonstrated that MCF7 cell line developed a more "aggressive" phenotype and behavior. Most of the proteins that were overexpressed in this experiment promoted the actin cytoskeleton reorganization that is involved in growth and metastatic dissemination of cancer cells. Some of these proteins are involved in the epithelial-mesenchymal transition (EMT) process (ACTBL2, TUBA4A, MYH14, CSPG5, PKM, UGDH, HSP90AA2, and MIF), in correlation with the energy metabolism reprogramming (PKM, UGDH), stress-response (HSP10, HSP70A1A, HSP90AA2), and immune and inflammatory response (MIF and ERp57-TAPBP). Almost all upregulated proteins in JTB downregulated condition promote viability, motility, proliferation, invasion, survival into a hostile microenvironment, metabolic reprogramming, and escaping of tumor cells from host immune control, leading to a more invasive phenotype for MCF7 cell line. Due to their downregulated condition, four proteins, such as CREBZF, KMT2B, SELENOS and CACNA1I are also involved in maintenance of the invasive phenotype of cancer cells, promoting cell proliferation, migration, invasion and tumorigenesis. Other downregulated proteins, such as MAZ, PLEKHG2, ENO1, TPI2, TOR2A, and CNNM1, may promote suppression of cancer cell growth, invasion, EMT, tumorigenic abilities, interacting with glucose and lipid metabolism, disrupting nuclear envelope stability, or suppressing apoptosis and developing anti-angiogenetic activities. Therefore, the main biological processes and pathways that may increase the tumorigenic potential of the MCF7 cells in JTB downregulated condition are related to the actin cytoskeleton organization, EMT, mitotic cell cycle, glycolysis and fatty acid metabolism, inflammatory response and macrophage activation, chemotaxis and migration, cellular response to stress condition (oxidative stress and hypoxia), transcription control, histone modification and ion transport.

Investigation of the effects of overexpression of jumping translocation breakpoint (JTB) protein in MCF7 cells for potential use as a biomarker in breast cancer.

Jumping translocation breakpoint (JTB) gene acts as a tumor suppressor or an oncogene in different malignancies, including breast cancer (BC), where it was reported as overexpressed. However, the molecular functions, biological processes and underlying mechanisms through which JTB protein causes increased cell growth, proliferation and invasion is still not fully deciphered. Our goal is to identify the functions of JTB protein by cellular proteomics approaches. MCF7 breast cancer cells were transfected with sense orientation of hJTB cDNA in HA, His and FLAG tagged CMV expression vector to overexpress hJTB and the expression levels were confirmed by Western blotting (WB). Proteins extracted from transfected cells were separated by SDS-PAGE and the in-gel digested peptides were analyzed by nano-liquid chromatography tandem mass spectrometry (nanoLC-MS/MS). By comparing the proteome of cells with upregulated conditions of JTB vs control and identifying the protein dysregulation patterns, we aim to understand the function of this protein and its contribution to tumorigenesis. Gene Set Enrichment Analysis (GSEA) algorithm was performed to investigate the biological processes and pathways that are associated with the JTB protein upregulation. The results demonstrated four significantly enriched gene sets from the following significantly upregulated pathways: mitotic spindle assembly, estrogen response late, epithelial-to-mesenchymal transition (EMT) and estrogen response early. JTB protein itself is involved in mitotic spindle pathway by its role in cell division/cytokinesis, and within estrogen response early and late pathways, contributing to discrimination between luminal and mesenchymal breast cancer. Thus, the overexpressed JTB condition was significantly associated with an increased expression of ACTNs, FLNA, FLNB, EZR, MYOF, COL3A1, COL11A1, HSPA1A, HSP90A, WDR, EPPK1, FASN and FOXA1 proteins related to deregulation of cytoskeletal organization and biogenesis, mitotic spindle organization, ECM remodeling, cellular response to estrogen, proliferation, migration, metastasis, increased lipid biogenesis, endocrine therapy resistance, antiapoptosis and discrimination between different breast cancer subtypes. Other upregulated proteins for overexpressed JTB condition are involved in multiple cellular functions and pathways that become dysregulated, such as tumor microenvironment (TME) acidification, the transmembrane transport pathways, glycolytic flux, iron metabolism and oxidative stress, metabolic reprogramming, nucleocytosolic mRNA transport, transcriptional activation, chromatin remodeling, modulation of cell death pathways, stress responsive pathways, and cancer drug resistance. The downregulated proteins for overexpressed JTB condition are involved in adaptive communication between external and internal environment of cells and maintenance between pro-apoptotic and anti-apoptotic signaling pathways, vesicle trafficking and secretion, DNA lesions repair and suppression of genes involved in tumor progression, proteostasis, redox state regulation, biosynthesis of macromolecules, lipolytic pathway, carbohydrate metabolism, dysregulation of ubiquitin-mediated degradation system, cancer cell immune escape, cell-to-cell and cell-to-ECM interactions, and cytoskeletal behaviour. There were no significantly enriched downregulated pathways.

Jumping translocation involving chromosome 13q in a patient with Crohn's Disease and inv(16)(p13.1q22)/CBFB-MYH11 acute myeloid leukemia.

Jumping translocations (JT) are rare chromosomal rearrangements caused by the translocation of one donor chromosome segment to two or more recipient chromosomes. In the setting of myeloid neoplasms, JT are typically associated with disease transformation to acute myeloid leukemia (AML), and studies to date have found JT to be associated with poor prognosis and short overall survival. However, JT have been only very rarely reported in AML associated with a favorable AML prognostic cytogenetic marker. Additionally, JT have infrequently been described in hematological malignancies associated with autoimmune diseases (AID) such as Crohn's Disease (CD). Here we describe a case of a 40-year-old female with a 24-year history of CD diagnosed with AML harbouring the inv(16)(p13.1q22)/CBFB-MYH11 rearrangement in conjunction with sideline clones containing trisomy 13, tetrasomy 13, and a JT of chromosome 13q12 jumping to 7q32 and 18p11.2. The patient attained molecular remission one month post diagnosis after induction 7 + 3 chemotherapy. Morphologic relapse of disease occurred 27 months post diagnosis. A second molecular remission was attained 3 months later after re-induction chemotherapy. The patient received a sibling bone marrow transplant 32 months post diagnosis and is currently in remission 7 months post allogeneic transplant. To the best of our knowledge, this case represents the first report of JT occurring in inv(16)(p13.1q22)/CBFB-MYH11 AML and the second of JT occurring in an AML patient with prior clinical history of CD. This case provides further insight into the rare occurrence of JT in AML, particularly AML with a favorable cytogenetic marker in conjunction with AID.

Jumping translocations of 1q in donor cell-derived myelodysplastic syndrome after cord blood transplantation: Case report and review of the literature.

Donor cell-derived leukemia and myelodysplastic syndrome (DCL) is a rare complication in patients after allogenic stem cell transplantation (SCT). Since 1971, numerous cases of DCL have been reported, but the detailed mechanisms of DCL are still unclear. A patient with jumping translocations (JTs) of 1q in umbilical cord blood donor cell-derived myelodysplastic syndrome (MDS), which likely occurred due to genetic alterations of TET2 and ASXL1 after cord blood transplantation (CBT), was examined in this study. Previously reported DCL cases after CBT that focused on the cytogenetic and molecular characteristics of these patients and patient outcome were reviewed. A total of 30 cases of DCL after CBT were identified between 2005 and 2018. The median time from CBT to the development of DCL was 16 months. The number of patients with DCL who were diagnosed with acute myeloid leukemia (AML) and MDS was 19 and 8, respectively. JTs were frequently observed in 5 of 27 DCL patients who had cytogenetic abnormalities, including our patient. Molecular abnormalities were described in 7 of the cases, and the most frequent abnormality was an NPM1 mutation. Other gene mutations that were usually found in de novo MDS or AML were observed in JT-DCL after CBT. From these results, chromosomal abnormalities such as JTs that occur subsequent to genetic alterations were seemed an important mechanisms underlying DCL onset in patients after CBT. Further molecular analyses regarding the genetic alterations of JTs are required to understand the pathogenesis of umbilical cord blood-derived JT-DCL.

Molecular cytogenetic pilot study on pleomorphic adenomas of salivary glands.

Pleomorphic adenomas (PAs) of salivary glands are the most frequent entity of solid parotid tumors. Nonetheless, their genetics is not yet well understood. Thus, the current study characterized 14 PAs using a unique combination of cytogenetic, molecular cytogenetic and/or molecular karyotyping based approaches. The current study applied G-banding based on trypsin treatment and Giemsa-staining in peripheral blood and tumor tissue. Additionally, fluorescence in situ hybridization was performed using whole chromosome painting or centromeric probes. Array-based comparative genomic hybridization was also conducted. In 5 of 14 cases, chromosomal and/or submicroscopic alterations were characterized. Balanced and unbalanced translocations, loss or gain of whole chromosomes and submicroscopic copy number alterations were detected. Furthermore, the first case of a so-called 'jumping translocation' in a PA was reported. The genes twist-related protein 1 and distal-less homeobox 5 were also involved in copy number variations in two PAs. In conclusion, approaches utilized in the current study are highly suited to characterize the genetic constitution of PAs.

A case of Philadelphia chromosome positive acute lymphoblastic leukemia with partial trisomy of chromosome 1q involving chromosome 13 as the acceptor-A novel cytogenetic finding.

The Philadelphia (Ph) chromosome is infrequently found in acute lymphoblastic leukemia and is associated with poor prognosis. We present a case of Ph chromosome positive B cell-acute lymphoblastic leukemia with the partial trisomy of chromosome 1q involving chromosome 13 as the acceptor which has never been reported in the English literature. Jumping translocation (JT) of chromosome 1 is rare and is associated with disease progression and poor prognosis. Herein, we report the first case of Ph chromosome positive B cell-acute lymphoblastic leukemia with coexisting jumping translocation of chromosome 1 leading to trisomy of chromosome 1q. Dismal prognosis associated with synchronous presence of a Ph chromosome and JT leading to a partial trisomy of chromosome 1q may carry significant prognostic and therapeutic implications. This may be an incidental finding and further studies with large patient cohorts and clinical outcomes are needed to definitively determine the predictive value of this cytogenetic finding.

Jumping translocations in myelodysplastic syndromes.

Jumping translocations (JT) have been identified in numerous malignancies, including leukemia, but infrequently in patients with myelodysplastic syndromes (MDS). The responsible genetic region has been mapped to the JTB gene at 1q21, but breakpoints involving other chromosomal loci, such as 3q and 11q, have been described as well. We have characterized the pathological and mutational landscape, and the clinical course of 6 new MDS patients with jumping mutations using chromosome genomic array testing (CGAT) and target gene panel next generation sequencing. In addition, we have performed a literature review for other MDS cases with JTs as defined by ISCN 2013. Results support the concept that MDS in patients with jumping translocations has a poor prognosis with a high risk of progression to leukemia, and suggest that these patients warrant aggressive therapy, including HCT, early in the disease course.

Jumping-like translocation-a rare chromosomal rearrangement in a patient with Burkitt lymphoma/leukemia.

Chromosomal translocations are acquired genetic rearrangements in human cancers. Jumping translocations are rare nonreciprocal rearrangements involving the same donor chromosome segment translocated to two or more recipient chromosomes. In this report, we describe a patient with Burkitt lymphoma/leukemia (BL) and a complex karyotype including a t(2;8)(p12;q24), copy-neutral loss of heterozygosity at 17p13.1-p13.3 and 19q13.1-q13.2, trisomy 20, and two uncommon chromosomal aberrations. The first uncommon aberration was a complex rearrangement of chromosome 15 (probably the consequence of chromothripsis) masked by an apparently balanced reciprocal translocation, t(11;15)(p11.2;q21). The second one was a special type of unbalanced "vice versa" jumping translocation, which involved the same acceptor chromosome arm (13q) and various donor chromosome segments. It is unclear whether both atypical rearrangements are the consequence of the TP53 alteration or whether assumed chromothripsis influenced the development of the jumping-like translocation. However, the presence of the t(11;15)(p11.2;q21) in all pathological cells suggests that it occurred in the early stage of the disease, whereas the jumping-like translocation, as an additional change, subsequently accelerated the progression of the disease.

Distinct karyotypes in two offspring of a man with jumping translocation karyotype 45,XY,der(16)t(16;22)(q24;q11.2), -22 [59]/45,XY,der(1)t(1;22)(p36;q11.2), -22 [11]/45,XY,der(22)t(22;22)(p13;q11.2), -22 [10].

We examined a man and his daughter, who both had different jumping translocation karyotypes. The man's wife was pregnant and had been referred for prenatal diagnosis of the fetus. The karyotype of the husband's peripheral blood lymphocytes was 45,XY,der(16)t(16;22)(q24;q11.2), -22 [59]/45,XY,der(1)t(1;22)(p36;q11.2), -22 [11]/45,XY,der(22)t(22;22)(p13;q11.2), -22 [10]. The karyotype of the daughter's peripheral blood lymphocytes was 45,XX,der(16)t(16;22)(q24;q11.2), -22 [45]/45,XX,der(9)t(9;22)(q34;q11.2), -22 [30]/45,XX,der(5)t(5;22)(q35;q11.2), -22 [25]. The wife and the fetus both had a normal karyotype. To the best of our knowledge, the present familial transmitted jumping translocation has not been previously described and the jumping translocation in the husband and daughter did not cause any phenotypic abnormalities.

Jumping translocation in a case of de novo infant acute myeloid leukemia.

An infant presented with fever and purulent discharge from the left ear, proptosis of the right eye, and hepatosplenomegaly. She was diagnosed with acute monoblastic leukemia on morphological and flowcytometric analysis of the bone marrow. Karyotyping showed a jumping translocation (JT) involving the long arm of chromosome 1 as the sole cytogenetic abnormality in 29 metaphases. The patient died within 2 months of diagnosis. The presence of JT in a de novo infant AML as a sole cytogenetic abnormality indicates its possible role in leukemogenesis unlike previous reports that have implicated its role in tumor progression only.

Characterization of the oncogenic function of centromere protein F in hepatocellular carcinoma.

Centromere protein F (CENPF) is an essential nuclear protein associated with the centromere-kinetochore complex and plays a critical role in chromosome segregation during mitosis. Up-regulation of CENPF expression has previously been detected in several solid tumors. In this study, we aim to study the expression and functional role of CENPF in hepatocellular carcinoma (HCC). We found CENPF was frequently overexpressed in HCC as compared with non-tumor tissue. Up-regulated CENPF expression in HCC was positively correlated with serum AFP, venous invasion, advanced differentiation stage and a shorter overall survival. Cox regression analysis found that overexpression of CENPF was an independent prognosis factor in HCC. Functional studies found that silencing CENPF could decrease the ability of the cells to proliferate, form colonies and induce tumor formation in nude mice. Silencing CENPF also resulted in the cell cycle arrest at G2/M checkpoint by down-regulating cell cycle proteins cdc2 and cyclin B1. Our data suggest that CENPF is frequently overexpressed in HCC and plays a critical role in driving HCC tumorigenesis.