Dataset Information

BCOR-CCNB3 fusion and BCOR internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

ABSTRACT: Undifferentiated round cell sarcomas (URCSs) usually remained unclassified due to lack of known genetic abnormalities. Herein, we retrospectively collected 5 cases of URCSs and sought to investigate their unique clinicopathologic and molecular features for providing more accurate classification. There were 2 males and 3 females with age ranged from 7 months to 17 years. The tumors were respectively located in the sacrum, fibula, neck, perineum or groin. Microscopically, all 5 tumors were composed of small-to-medium sized cells with primitive morphology and variable cellularity, distributed within loose myxoid or collagenized fibroid stroma. These tumors lacked specific immunophenotypes and known gene rearrangements. However, the expression levels of CD99 and cyclin D1 were variable. RNA-sequencing data identified one BCOR-CCNB3 gene fusion-positive sarcoma occurring in the sacrum of a 17-year-old male patient. Whole genome sequencing analysis detected BCOR exon 15-internal tandem duplication (BCOR-ITD) in the tumor arising in the groin of one 7-month-old female infant. No specific gene abnormalities were found in the other 3 cases. Interestingly, a morphological and immunohistochemical overlap existed between BCOR-rearrangement tumor and BCOR-ITD-positive tumor, including areas with hypercellularity alternating with hypocellularity, a mixture of round cells and focal spindle cells, pale nuclear chromatin, inconspicuous nucleoli and abundant myxoid matrix, diffuse strong cyclin D1 expression, relatively strong expression of CD99 but lower than that in Ewing sarcoma, and a low Ki-67 proliferation index of about 10%. Our findings demonstrated a significant link between genetic aberration and histopathologic appearances, thus supporting the crucial role of genetic characteristics in accurate clinicopathological classification.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6789234 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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<i>BCOR-CCNB3</i> fusion and <i>BCOR</i> internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

Yang Yang Y Shi Huijuan H Zheng Jiaxin J Gao Huabin H Zhen Tiantian T Zhang Fenfen F Han Anjia A

American journal of translational research 20190915 9

Undifferentiated round cell sarcomas (URCSs) usually remained unclassified due to lack of known genetic abnormalities. Herein, we retrospectively collected 5 cases of URCSs and sought to investigate their unique clinicopathologic and molecular features for providing more accurate classification. There were 2 males and 3 females with age ranged from 7 months to 17 years. The tumors were respectively located in the sacrum, fibula, neck, perineum or groin. Microscopically, all 5 tumors were compose ...[more]

PMID: 31632552

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Project description:Soft tissue undifferentiated round cell sarcoma (URCS) occurring in infants is a heterogenous group of tumors, often lacking known genetic abnormalities. On the basis of a t(10;17;14) karyotype in a pelvic URCS of a 4-month-old boy showing similar breakpoints with clear cell sarcoma of kidney (CCSK), we have investigated the possibility of shared genetic abnormalities in CCSK and soft tissue URCS. Most CCSKs are characterized by BCOR exon 16 internal tandem duplications (ITDs), whereas a smaller subset shows YWHAE-NUTM2B/E fusions. Because of overlapping clinicopathologic features, we have also investigated these genetic alterations in the so-called primitive myxoid mesenchymal tumor of infancy (PMMTI). Among the 22 infantile URCSs and 7 PMMTIs selected, RNA sequencing was performed in 5 and 2 cases, with frozen tissue, respectively. The remaining cases with archival material were tested for YWHAE-NUTM2B/E by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction (RT-PCR), and BCOR ITD by PCR. A control group of 4 CCSKs and 14 URCSs in older children or adults without known gene fusion and 20 other sarcomas with similar histomorphology or age at presentation were also tested. A YWHAE-NUTM2B fusion was confirmed in the index case by FISH and RT-PCR, whereas BCOR ITD was lacking. An identical YWHAE-NUTM2B fusion was found in another URCS case of a 5-month-old girl with a back lesion. The remaining cases and control group lacked YWHAE gene rearrangements; instead, consistent BCOR ITDs, similar to CCSK, were found in 15/29 (52%) infantile sarcoma cases (9/22 infantile URCS and 6/7 PMMTI). In the control cohort, BCOR ITD was found only in 3 CCSK cases but not in the other sarcomas. Histologically, URCS with both genotypes and PMMTI shared significant histologic overlap, with uniform small blue round cells with fine chromatin and indistinct nucleoli. A prominent capillary network similar to CCSK, rosette structures, and varying degree of myxoid change were occasionally seen. BCOR ITD-positive tumors occurred preferentially in the somatic soft tissue of the trunk, abdomen, and head and neck, sparing the extremities. RNAseq showed high BCOR mRNA levels in BCOR ITD-positive cases, compared with other URCSs. In summary, we report recurrent BCOR exon 16 ITD and YWHAE-NUTM2B fusions in half of infantile soft tissue URCS and most PMMTI cases, but not in other pediatric sarcomas. These findings suggest a significant overlap between infantile URCS and CCSK, such as age at presentation, histologic features, and genetic signature, thus raising the possibility of a soft tissue counterpart to CCSK.

Project description:Small blue round cell tumors (SBRCTs) are a heterogenous group of tumors that are difficult to diagnose because of overlapping morphologic, immunohistochemical, and clinical features. About two-thirds of EWSR1-negative SBRCTs are associated with CIC-DUX4-related fusions, whereas 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 man, we identified a novel BCOR-MAML3 chimeric fusion, which was validated by reverse transcription polymerase chain reaction and fluorescence in situ hybridization techniques. We then screened a total of 75 SBRCTs lacking EWSR1, FUS, SYT, CIC, and BCOR-CCNB3 abnormalities for BCOR break-apart probes by fluorescence in situ hybridization 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, whereas 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 with classic Ewing's sarcoma or CIC-DUX4-positive SBRCTs. The clinicopathologic features of the SBRCTs 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.

Project description:BCOR-CCNB3 sarcoma (BCS) is a recently defined genetic entity among undifferentiated round cell sarcomas, which was initially classified as and treated similarly to the Ewing sarcoma (ES) family of tumors. In contrast to ES, BCS shows consistent BCOR overexpression, and preliminary evidence suggests that these tumors share morphologic features with other tumors harboring BCOR genetic alterations, including BCOR internal tandem duplication (ITD) and BCOR-MAML3. To further investigate the pathologic features, clinical behavior, and their relationship to other round cell sarcomas, we collected 36 molecularly confirmed BCSs for a detailed histologic and immunohistochemical analysis. Four of the cases were also analyzed by RNA sequencing (RNAseq). An additional case with BCOR overexpression but negative CCNB3 abnormality showed a novel KMT2D-BCOR fusion by targeted RNAseq. The patients ranged in age from 2 to 44 years old (mean and median, 15), with striking male predominance (M:F=31:5). The tumor locations were slightly more common in bone (n=20) than soft tissue (n=14), with rare visceral (kidney, n=2) involvement. Histologically, BCS showed a spectrum of round to spindle cells with variable cellularity, monomorphic nuclei and fine chromatin pattern, delicate capillary network, and varying amounts of myxoid or collagenous stroma. The morphologic features and immunoprofile showed considerable overlap with other round cell sarcomas with BCOR oncogenic upregulation, that is, BCOR-MAML3 and BCOR ITD. Follow-up available in 22 patients showed a 5-year overall survival of 72%, which was relatively similar to ES (79%, P=0.738) and significantly better than CIC-DUX4 sarcomas (43%, P=0.005) control groups. Local recurrences occurred in 6 patients and distant metastases (lung, soft tissue/bone, pancreas) in 4. Seven of 9 cases treated with an ES chemotherapy regimen with evaluable histologic response showed >60% necrosis in posttherapy resections. Unsupervised clustering by RNAseq data revealed that tumors with BCOR genetic alterations, including BCOR-CCNB3, BCOR-MAML3, and BCOR ITD, formed a tight genomic group distinct from ES and CIC-rearranged sarcomas.

Dataset Information

BCOR-CCNB3 fusion and BCOR internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

Publications

<i>BCOR-CCNB3</i> fusion and <i>BCOR</i> internal tandem duplication in undifferentiated round cell sarcoma: a pathologic and molecular study of 5 cases.

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