Correlation of t(14;18) translocation breakpoint site with clinical characteristics in follicular lymphoma.

BACKGROUND: t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3'MBR and 5'mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma. PATIENTS AND METHODS: We included patients diagnosed with follicular lymphoma who received at least 1 cycle of systemic treatment and had the t(14;18)(q32;q21) translocation detected by polymerase chain reaction (PCR) at MBR, mcr or 3'MBR prior to first treatment. Among patients with different breakpoints, sex, age, disease grade, stage, B-symptoms, follicular lymphoma international prognostic index (FLIPI), presence of bulky disease, progression free survival and overall survival were compared. RESULTS: Of 84 patients, 63 had breakpoint at MBR, 17 at mcr and 4 at 3'MBR. At diagnosis, the MBR group had a significantly lower disease stage than the mcr group. Although not significant, in the MBR group we found a higher progression-free survival (PFS) and overall survival (OS), lower grade, age, FLIPI, and less B-symptoms. CONCLUSIONS: Compared to patients with mcr breakpoint, those with MBR breakpoint seem to be characterised by more favourable clinical characteristics. However, a larger study would be required to support our observation.

EWSR1 maintains centromere identity.

The centromere is essential for ensuring high-fidelity transmission of chromosomes. CENP-A, the centromeric histone H3 variant, is thought to be the epigenetic mark of centromere identity. CENP-A deposition at the centromere is crucial for proper centromere function and inheritance. Despite its importance, the precise mechanism responsible for maintenance of centromere position remains obscure. Here, we report a mechanism to maintain centromere identity. We demonstrate that CENP-A interacts with EWSR1 (Ewing sarcoma breakpoint region 1) and EWSR1-FLI1 (the oncogenic fusion protein in Ewing sarcoma). EWSR1 is required for maintaining CENP-A at the centromere in interphase cells. EWSR1 and EWSR1-FLI1 bind CENP-A through the SYGQ2 region within the prion-like domain, important for phase separation. EWSR1 binds to R-loops through its RNA-recognition motif in vitro. Both the domain and motif are required for maintaining CENP-A at the centromere. Therefore, we conclude that EWSR1 guards CENP-A in centromeric chromatins by binding to centromeric RNA.

Cutaneous syncytial myoepithelioma with folliculocentric growth and EWSR1 gene rearrangement: A case report.

Cutaneous syncytial myoepithelioma is a tumor type that was initially reported in 2013 as a syncytial variant of cutaneous myoepithelioma characterized by intradermal nodular proliferation of oval to spindle-shaped tumor cells in solid and syncytial patterns. Fusion of genes Ewing sarcoma breakpoint region 1 / EWS RNA binding protein 1 (EWSR1) and pre-B cell leukemia homeobox 3 (PBX3) is found in approximately 90% of the cases. We report a case of cutaneous syncytial myoepithelioma with diagnostic difficulty due to folliculocentric morphology and atypical immunohistochemical results, including diffuse positivity of α-smooth muscle actin and claudin 4 and negative immunoreactions for epithelial membrane antigen and S100 protein. In the present case, fluorescence in situ hybridization study demonstrated EWSR1 rearrangement. We further provide a discussion of differential diagnoses with a review of relevant literature.

Spinal cord astroblastoma with EWSR1-BEND2 fusion classified as HGNET-MN1 by methylation classification: a case report.

The most recurrent fusion of central nervous system high-grade neuroepithelial tumor with MN1 alteration (HGNET-MN1) is MN1 rearrangement. Here, we report the case of a 36-year-old man with spinal cord astroblastoma showing Ewing Sarcoma breakpoint region 1/EWS RNA-binding protein 1 (EWSR1)-BEN domain-containing 2 (BEND2) fusion. The patient presented with back pain, gait disturbance and dysesthesia in the lower extremities and trunk. Magnetic resonance imaging showed an intramedullary tumor at the T3-5 level, displaying homogeneous gadolinium enhancement. Partial tumor removal was performed with laminectomy. Histological examinations demonstrated solid growth of epithelioid tumor cells showing high cellularity, a pseudopapillary structure, intervening hyalinized fibrous stroma, and some mitoses. Astroblastoma was diagnosed, classified as HGNET-MN1 by the German Cancer Research Center methylation classifier. MN1 alteration was not detected by fluorescence in situ hybridization (FISH), but EWSR1-BEND2 fusion was detected by FISH and RNA sequencing. Previously, a child with EWSR1-BEND2 fusion-positive spinal astroblastoma classified as HGNET-MN1 was reported. In conjunction with that, the present case provides evidence that EWSR1-BEND2 fusion is identified in the entity of HGNET-MN1. Taken together, the BEND2 alteration rather than MN1 may determine the biology of a subset of the central nervous system HGNET-MN1 subclass.

Ewing sarcoma of the jejunum: A case report and literature review.

BACKGROUND: Ewing sarcomas (ESs) are highly aggressive malignancy and are predominant in the long bones of extremities of children and young adults with a slight male predilection and rarely presents at extra skeletal locations. CASE SUMMARY: A 55-year-old woman came to our hospital after finding elevated tumor biomarkers during her physical examination. Her enhanced computed tomography scan showed a jejunal mass. The patient underwent laparoscopic enterectomy. The mass was later diagnosed as ES, evidenced by fluorescence in situ hybridization whereby the GLP ES breakpoint region 1 probe was used, showing that more than 10% of the cells showed a red-green-yellow signal proving the breakpoint rearrangement of the ES breakpoint region 1 gene in chromosome 22. CONCLUSION: We describe a case of localized ES at the jejunum in China based on the literature.

Intracranial non-myxoid angiomatoid fibrous histiocytoma with EWSR1-CREB1 transcript fusion treated with doxorubicin: A case report.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that has only been reported in the central nervous system in case reports. After surgery, patients exhibit tumor recurrence. Pathological diagnosis of AHF remains difficult, especially in sites other than skin. AFH can harbor characteristic translocations implying that the Ewing sarcoma breakpoint region 1 gene (EWSR1) fuses with the transcription factor cyclic AMP response element binding (CREB) family genes. Doxorubicin is a chemotherapy that has previously been used successfully in two metastatic soft tissue AFH cases but never in intracranial AFH. The present report describes a case of an adult with a progressive classical intracranial non-myxoid AFH with ESWR1-CREB1 transcript fusion 4 years after surgery. The patient was treated with doxorubicin as a single agent chemotherapy. This treatment resulted in a prolonged stable disease 15 months after treatment discontinuation. This is the first reported case of a treatment with doxorubicin in an adult with progressive intracranial AFH with ESWR1-CREB1 transcript fusion which was sustained after treatment discontinuation.

Analysis for common chromosomal breakpoint regions among 586 carriers of reciprocal translocations from Henan Province / 中华医学遗传学杂志

Objective@#To determine the frequency, common chromosomal karyotypes and breakpoints, and involved regions among carriers of reciprocal translocations from Henan Province, and to explore the influence of common breakpoint regions on pregnancy and fetal development.@*Methods@#For 586 carriers of reciprocal translocations, the above features were retrospectively analyzed.@*Results@#The 586 reciprocal translocations were identified among 62 477 subjects, which yielded a frequency of 0.94%. Among these, 572 (0.92%) had abnormal fertility, and 14 (0.02%) had a history of abnormal fetal development. Statistical analysis showed that chromosomes 1, 4, 7 and 11 were most frequently involved, with t(11; 22)(q25; q13) being the most common type of translocation. In total 437 breakpoint regions were identified, with 11q23, 22q13 and 1p36 being most frequently involved, which resulted in infertility, abortion, embryo death, congenital malformation, development delay, mental retardation or a normal phenotype.@*Conclusion@#Above results indicated a 0.92% carrier rate for reciprocal chromosomal translocations in Henan. The location of breakpoint regions may affect the pregnancy and/or fetal development. Discovery of such regions may enable more accurate genetic, reproductive and developmental counseling for carriers, and provide reference for delineation of function and pathogenetic mechanism of the relevant genes.

Chromosome-level genome assembly for giant panda provides novel insights into Carnivora chromosome evolution.

BACKGROUND: Chromosome evolution is an important driver of speciation and species evolution. Previous studies have detected chromosome rearrangement events among different Carnivora species using chromosome painting strategies. However, few of these studies have focused on chromosome evolution at a nucleotide resolution due to the limited availability of chromosome-level Carnivora genomes. Although the de novo genome assembly of the giant panda is available, current short read-based assemblies are limited to moderately sized scaffolds, making the study of chromosome evolution difficult. RESULTS: Here, we present a chromosome-level giant panda draft genome with a total size of 2.29 Gb. Based on the giant panda genome and published chromosome-level dog and cat genomes, we conduct six large-scale pairwise synteny alignments and identify evolutionary breakpoint regions. Interestingly, gene functional enrichment analysis shows that for all of the three Carnivora genomes, some genes located in evolutionary breakpoint regions are significantly enriched in pathways or terms related to sensory perception of smell. In addition, we find that the sweet receptor gene TAS1R2, which has been proven to be a pseudogene in the cat genome, is located in an evolutionary breakpoint region of the giant panda, suggesting that interchromosomal rearrangement may play a role in the cat TAS1R2 pseudogenization. CONCLUSIONS: We show that the combined strategies employed in this study can be used to generate efficient chromosome-level genome assemblies. Moreover, our comparative genomics analyses provide novel insights into Carnivora chromosome evolution, linking chromosome evolution to functional gene evolution.

CircRNAs Are Here to Stay: A Perspective on the MLL Recombinome.

Chromosomal translocations harbored by cancer genomes are important oncogenic drivers. In MLL rearranged acute leukemia (MLLre) MLL/KMT2A fuses with over 90 partner genes. Mechanistic studies provided clues of MLL fusion protein leukemogenic potential, but models failed to fully recapitulate the disease. Recently, expression of oncogenic fusion circular RNAs (f-circ) by MLL-AF9 fusion was proven. This discovery, together with emerging data on the importance and diversity of circRNAs formed the incentive to study the circRNAs of the MLL recombinome. Through interactions with other RNAs, such as microRNAs, and with proteins, circRNAs regulate cellular processes also related to cancer development. CircRNAs can translate into functional peptides too. MLL and most of the 90 MLL translocation partners do express circRNAs and exploration of our RNA-seq dataset of sorted blood cell populations provided new data on alternative circular isoform generation and expression variability of circRNAs of the MLL recombinome. Further, we provided evidence that rearrangements of MLL and three of the main translocation partner genes can impact circRNA expression, supported also by preliminary observations in leukemic cells. The emerging picture underpins the view that circRNAs are worthwhile to be considered when studying MLLre leukemias and provides a new perspective on the impact of chromosomal translocations in cancer cells at large.

Intra-Extracranial Primary Clear Cell Sarcoma: The First Report and Review of the Literature.

BACKGROUND: Clear cell sarcoma (CCS) is a rare malignant soft tissue tumor with poor prognosis owing to metastasis and insensitive response to chemotherapy and radiotherapy. METHODS: We first searched PubMed and Embase using the terms "clear cell sarcoma," "malignant melanoma of soft tissue," "head," and "neck." In the 15 articles selected for literature review, only 27% (4/15) of patients were diagnosed with primary CCS of the head. Pathologically, those tumors arose from either the scalp or the superficial temporal fascia, but none invaded the skull and brain. Next, the search was performed in the same database using the terms "clear cell sarcoma," "malignant melanoma of soft tissue," and "bone," and only 24 articles were selected. RESULTS: In the case reported here, a 36-year-old woman was found to have a palpable mass located at the left temporal-occipital region, and surgical finding confirmed the invasion into the skull and the brain. The diagnosis of primary CCS was made because of the detection of t(12;22)(q13;q12) in >50% of tumor cells by fluorescence in situ hybridization, and metastasis to the lymph nodes and lungs was discovered by postoperative positron emission tomography-computed tomography. CONCLUSIONS: To the best of our knowledge, this is the first case of primary central nervous system CCS. Primary CCS may involve the skull and should be one of the differential diagnoses for intra-extracranial communicating tumors. Further research on biological characteristics and molecular targeted therapy of CCS are needed to improve its poor prognosis.

Translocation-Related Sarcomas.

Chromosomal translocations are observed in approximately 20% of soft tissue sarcomas (STS). With the advances in pathological examination technology, the identification of translocations has enabled precise diagnoses and classifications of STS, and it has been suggested that the presence of and differences in translocations could be prognostic factors in some translocation-related sarcomas. Most of the translocations in STS were not regarded as targets of molecular therapies until recently. However, trabectedin, an alkylating agent, has shown clinical benefits against translocation-related sarcoma based on a modulation of the transcription of the tumor's oncogenic fusion proteins. Many molecular-targeted drugs that are specific to translocations (e.g., anaplastic lymphoma kinase and tropomyosin kinase related fusion proteins) have emerged. The progress in gene technologies has allowed researchers to identify and even induce new translocations and fusion proteins, which might become targets of molecular-targeted therapies. In this review, we discuss the clinical significance of translocation-related sarcomas, including their diagnoses and targeted therapies.

Combined analysis of gene expression and genome binding profiles identified potential therapeutic targets of ciclopirox in Ewing sarcoma.

Ciclopirox (CPX) is a synthetic antifungal drug that is mainly used to treat dermatomycoses. The aim of the present study was to determine whether CPX could influence Ewing sarcoma progression. The present study suggested that CPX treatment may inhibit Ewing sarcoma (ES) progression through Ewing sarcoma breakpoint region 1­Friend leukemia integration 1 (EWS­FLI1), a common fusion transcript structure in patients with ES. To determine the underlying mechanisms of ES progression, cross analysis was conducted on three high­throughput genome or transcript me datasets from the Gene Expression Omnibus. The results indicated that CPX may inhibit ES growth by affecting vasculature development and DNA replication. A combination of genome­wide expression and binding profiles revealed several potential targets for CPX in ES, including collagen type I α2 chain, N­myc proto­oncogene and transforming growth factor ß1, which contained significantly enriched binding peaks of FLI1. In addition, network analysis, including a protein­protein interaction network and a transcription regulatory network, provided further detailed information about the roles of CPX in ES. This study may provide a novel solution for ES treatment and may also aid in improving its prognosis.

Peripheral primitive neuroectodermal tumor of the kidney in a 51-year-old female following breast cancer: A case report and review of the literature.

Peripheral primitive neuroectodermal tumor/Ewing's sarcoma (pPNET/EWS) is an aggressive type of sarcoma that is rarely observed in the kidney. pPNET of the kidney principally occurs in young patients (<50 years old) and is very rare in older patients (≥50 years old). Additionally, only six cases of pPNET of the kidney have been reported in the literature in older patients (≥50 years old), and pPNET as a secondary primary tumor has rarely been reported. The current study presents a case of renal pPNET in a 51-year-old female who had been surgically treated for breast carcinoma and administered with adjuvant chemotherapy five years prior to hospitalization for pPNET. A computed tomography scan identified a tumor in the lower pole of the right kidney, which was treated by nephrectomy. Immunohistochemistry demonstrated diffuse, strong membranous positivity for cluster of differentiation (CD)99, positive nuclear staining for friend leukemia integration 1, and negative staining for Wilms' tumor 1 and other markers. Fluorescence in situ hybridization (FISH) analysis of the EWS breakpoint region 1 (EWSR1) demonstrated the characteristic EWSR1 translocation. The patient declined chemotherapy or radiotherapy but accepted traditional Chinese medicine. No evidence of recurrence was observed eight months after diagnosis. Only two cases of renal pPNET with a history of an earlier or synchronous primary cancer were reported in the literature from the USA and Germany, respectively. To the best of our knowledge, the present case is the first FISH-confirmed renal pPNET in an older patient following breast adenocarcinoma.

Central type primitive neuroectodermal tumor/neuroblastoma of the uterus: a case report.

We encountered a 63-year-old woman who had a uterine tumor with peritoneal dissemination and para-aortic lymph node metastasis. Microscopic specimens of the tumor showed a small blue round-cell tumor. Immunohistochemistry showed cells to be negative for cytokeratin AE1/3, desmin, myogenin, CD10, CD34, and CD99, focal positive for vimentin, and positive for muscle-specific actin (HHF-35), neurofilament, synaptophysin and CD56. Fluorescence in situ hybridization revealed no split signal showing Ewing sarcoma breakpoint region 1 gene translocation. Deletion of 1p36 was identified in 30% of the tumor cells. These findings are thought to be equivalent to central type primitive neuroectodermal tumors/neuroblastoma. Cytoreductive debulking surgery followed by chemotherapy, including cyclophosphamide, vincristine and adriamycin, resulted in complete remission. She has no evidence of disease at 24 months after surgery.

DETECTION OF BCL-2 GENE MAJOR BREAKPOINTREGION REARRANGEMENT IN HUMAN B-CELL LYMPHOMAS / 药物分析学报

Objective To investigate the frequency of t(14;18) in different subtypes of B-cell lymphomas and the ability of the polymerase chain reaction(PCR) to detect this rearrangement in frozen samples. Methods 107 cases of B-cell lymphomas were studied using DNA extracted from fresh-frozen tissues. The DNA samples were amplified by PCR for bcl-2 MBR/JH. The products of bcl-2/JH rearrangement were hybridized with an internal olignucleotide probe of bel-2 MBR. Results The rearranged bel-2MBR/JH gene was detected in 13 of the 25(52. 0％) follicular cen ter lymphomas, according to REAL classification: 8 of 11(72. 7％) grade 1 , 2 of 5(40. 0％) grade Ⅱ , and 3 of 90 (33. 3％) grade Ⅲ. 17 of 82(20. 8％) cases of diffuse large B-cell lympbomas were found to have detectable bcl-2 MBR/JH rearrangement. Conclusion The frequency of bcl-2 MBR/JH rearrangement in diffuse large B-cell lym phomas is significantly lower than those in follicular center lymphomas(χ2=9. 28, P ＜0. 005), suggesting that bcl 2/JH rearrangements occur mainly in follicular center lymphomas. In addition, the result of reconstruction experi ments suggest that amplification of bcl-2 MBR/JH rearrangements by PCR is both sensitive and specific for detection of t (14 ; 18 ) translocation.