Novel ZC3H7B‐BCOR, MEAF6‐PHF1, and EPC1‐PHF1 fusions in ossifying fibromyxoid tumors—molecular characterization shows genetic overlap with endometrial stromal sarcoma

Antonescu, Cristina R.; Sung, Yun‐Shao; Chen, Chun-Liang; Zhang, Lei; Chen, Hsiao‐Wei; Singer, Samuel; Agaram, Narasimhan P.; Sboner, Andrea; Fletcher, Christopher D.�M.

doi:10.1002/gcc.22132

Cited by 150 publications

(170 citation statements)

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“…The subsequent FISH screening for potential partners identified BCOR-MAML3 fusion in an additional case, while the remaining 6 cases showed no abnormalities in MAML3 . Upon review of the literature for additional BCOR gene partners we identified ZC3H7B as a potential candidate, having been described in BCOR-ZC3H7B fusions in other sarcomas 20,25 . Thus we screened the remaining 6 BCOR -rearranged cases for ZC3H7B gene break-apart by FISH and found 2 positive cases.…”

Section: Resultsmentioning

confidence: 99%

“…17 FusionSeq is a computational method that has been successfully applied to paired-end RNA-seq data for the identification of chimeric fusion transcripts. 9,18–20 Briefly, in a first step, paired end reads mapping to different genes were used to identify potential chimeric candidates. A cascade of filters, each taking into account different sources of noise in RNA-sequencing experiments, was then applied to remove spurious fusion transcripts.…”

Section: Methodsmentioning

confidence: 99%

“…FISH analysis was performed on interphase nuclei from paraffin-embedded 4 µm sections applying bacterial artificial chromosomes (BAC clones), flanking BCOR on chromosome Xp11.4, MAML3 on chromosome 4q31.1, ZC3H7B on chromosome 22q13 20 and CCNB3 on chromosome Xp11.22 (Supplementary Table 1). BAC clones were chosen according to the UCSC genome browser (http://genome.ucsc.edu) and were obtained from BACPAC sources of Children’s Hospital of Oakland Research Institute (CHORI) (Oakland, CA) (http://bacpac.chori.org).…”

Section: Methodsmentioning

confidence: 99%

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Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

Specht

Zhang

Sung

et al. 2016

American Journal of Surgical Pathology

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141

111

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Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose due to overlapping morphologic, immunohistochemical and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4 related fusions, while another small subset shows BCOR-CCNB3 X-chromosomal paracentric inversion. Applying paired-end RNA sequencing to an SBRCT index case of a 44 year-old male, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by RT-PCR and FISH techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC and BCOR-CCNB3 abnormalities, for BCOR break-apart probes by FISH to detect potential recurrent BCOR gene rearrangements, outside the typical X-chromosomal inversion. Indeed, 8/75 (11%) SBRCTs showed distinct BCOR gene rearrangements, with 2 cases each showing either a BCOR-MAML3 or the alternative ZC3H7B-BCOR fusion, while no fusion partner was detected in the remaining 4 cases. Gene expression of the BCOR-MAML3 positive index case showed a distinct transcriptional profile with upregulation of HOX-gene signature, compared to classic Ewing sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SRBCTs with alternative BCOR rearrangements were also compared with a group of BCOR-CCNB3 inversion positive cases, combining 11 from our files with a meta-analysis of 42 published cases. The BCOR-CCNB3-positive tumors occurred preferentially in children and in bone, in contrast to alternative BCOR-rearranged SBRCTs which presented in young adults, with a variable anatomic distribution. Furthermore BCOR-rearranged tumors often displayed spindle cell areas, either well-defined in intersecting fascicles or blending with the round cell component, which appears distinct from most other fusion-positive SBRCTs and shares histologic overlap with poorly differentiated synovial sarcoma.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

Specht

Zhang

Sung

et al. 2016

American Journal of Surgical Pathology

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141

111

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“…ING5 is a part of the ING (inhibitor of growth) family, whose founding members were initially identified as inhibitors of cell growth [122]. The EAF6 gene is rearranged in endometrial stromal sarcoma [123,124]. Thus, like MOZ and MORF, the BRPF1-ING5-EAF6 subcomplex plays a direct role in cancer.…”

Section: Brpf1 and Its Paralogs In Animal Development And Human Diseasementioning

confidence: 99%

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

101

128

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Lysine residues are subject to many forms of covalent modification and one such modification is acetylation of the ε-amino group. Initially identified on histone proteins in the 1960s, lysine acetylation is now considered as an important form of post-translational modification that rivals phosphorylation. However, only about a dozen of human lysine acetyltransferases have been identified. Among them are MOZ (monocytic leukemia zinc finger protein; a.k.a. MYST3 and KAT6A) and its paralog MORF (a.k.a. MYST4 and KAT6B). Although there is a distantly related protein in Drosophila and sea urchin, these two enzymes are vertebrate-specific. They form tetrameric complexes with BRPF1 (bromodomain- and PHD finger-containing protein 1) and two small non-catalytic subunits. These two acetyltransferases and BRPF1 play key roles in various developmental processes; for example, they are important for development of hematopoietic and neural stem cells. The human KAT6A and KAT6B genes are recurrently mutated in leukemia, non-hematologic malignancies, and multiple developmental disorders displaying intellectual disability and various other abnormalities. In addition, the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma. Therefore, these two acetyltransferases and their partner BRPF1 are important in animal development and human disease.

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“…The PHF1 protein acts as an accessory component of the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 Lys27 (H3K27me3) to repress gene expression. 27 As PHF1 rearrangements are believed to be important for tumor development in other sarcomas, 28,29 it is not unlikely that loss of PHF1 function may also lead to epigenetic deregulation of PRC2 target genes.…”

Section: Discussionmentioning

confidence: 99%

RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts

Hofvander

Tayebwa

Nilsson

et al. 2015

Laboratory Investigation

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Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with 450 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.

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Novel ZC3H7B‐BCOR, MEAF6‐PHF1, and EPC1‐PHF1 fusions in ossifying fibromyxoid tumors—molecular characterization shows genetic overlap with endometrial stromal sarcoma

Cited by 150 publications

References 30 publications

Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

Novel BCOR-MAML3 and ZC3H7B-BCOR Gene Fusions in Undifferentiated Small Blue Round Cell Sarcomas

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts

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