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Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information.

ABSTRACT: Undifferentiated solid tumors with small blue round cell histology and expression of CD99 mostly resemble Ewing sarcoma. However, they also may include other tumors such as mesenchymal chondrosarcoma, synovial sarcoma, or small cell osteosarcoma. Definitive classification usually requires detection of entity-specific mutations. While this approach identifies the majority of Ewing sarcomas, a subset of lesions remains unclassified and, therefore, has been termed "Ewing-like sarcomas" or small blue round cell tumors not otherwise specified. We developed an approach for further characterization of small blue round cell tumors not otherwise specified using an array-based DNA-methylation profiling approach. Data were analyzed by unsupervised clustering and t-distributed stochastic neighbor embedding analysis and compared with a reference methylation data set of 460 well-characterized prototypical sarcomas encompassing 18 subtypes. Verification was performed by additional FISH analyses, RNA sequencing from formalin-fixed paraffin-embedded material or immunohistochemical marker analyses. In a cohort of more than 1,000 tumors assumed to represent Ewing sarcomas, 30 failed to exhibit the typical EWS translocation. These tumors were subjected to methylation profiling and could be assigned to Ewing sarcoma in 14 (47%), to small blue round cell tumors with CIC alteration in 6 (20%), to small blue round cell tumors with BCOR alteration in 4 (13%), to synovial sarcoma and to malignant rhabdoid tumor in 2 cases each. One single case each was allotted to mesenchymal chondrosarcoma and adamantinoma. 12/14 tumors classified as Ewing sarcoma could be verified by demonstrating either a canonical EWS translocation evading initial testing, by identifying rare breakpoints or fusion partners. The methylation-based assignment of the remaining small blue round cell tumors not otherwise specified also could be verified by entity-specific molecular alterations in 13/16 cases. In conclusion, array-based DNA-methylation analysis of undifferentiated tumors with small blue round cell histology is a powerful tool for precisely classifying this diagnostically challenging tumor group.

SUBMITTER: Koelsche C

PROVIDER: S-EPMC7484949 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information.

Koelsche Christian C Hartmann Wolfgang W Schrimpf Daniel D Stichel Damian D Jabar Susanne S Ranft Andreas A Reuss David E DE Sahm Felix F Jones David T W DTW Bewerunge-Hudler Melanie M Trautmann Marcel M Klingebiel Thomas T Vokuhl Christian C Gessler Manfred M Wardelmann Eva E Petersen Iver I Baumhoer Daniel D Flucke Uta U Antonescu Cristina C Esteller Manel M Fröhling Stefan S Kool Marcel M Pfister Stefan M SM Mechtersheimer Gunhild G Dirksen Uta U von Deimling Andreas A

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20180323 8

Undifferentiated solid tumors with small blue round cell histology and expression of CD99 mostly resemble Ewing sarcoma. However, they also may include other tumors such as mesenchymal chondrosarcoma, synovial sarcoma, or small cell osteosarcoma. Definitive classification usually requires detection of entity-specific mutations. While this approach identifies the majority of Ewing sarcomas, a subset of lesions remains unclassified and, therefore, has been termed "Ewing-like sarcomas" or small blu ...[more]

PMID: 29572501

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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:Background: Chromosomal abnormalities play an important role in the diagnosis and prognosis of patients with myelodysplastic syndromes (MDSs). The single-nucleotide polymorphism array (SNP-A) technique has gained popularity due to its improved resolution compared to that of metaphase cytogenetic (MC) analysis. Methods: A total of 376 individuals were recruited from two medical centers in China, including 350 patients and 26 healthy individuals. Among these patients, 200 were diagnosed with de novo MDS, 25 with myeloproliferative neoplasm (MPN), 63 with primary acute myeloid leukemia (AML), and 62 with idiopathic cytopenia of undetermined significance (ICUS). We evaluated the significance of abnormal chromosomes detected by SNP-A in the diagnosis and prognosis of MDS-related disorders. Results: (1) When certain chromosomal abnormalities could not be detected by conventional MC methods, these abnormalities could be detected more efficiently by the SNP-A method. With SNP-A, the detection rates of submicroscopic or cryptic aberrations in the MDS, MPN, and AML patients with normal MC findings were 32.8, 30.8, and 30%, respectively. (2) The chromosomal abnormalities detected by SNP-A had a very important value for the prognosis of patients with MDSs, especially in the low-risk group. The survival of patients with abnormal chromosomes detected by SNP-A was significantly lower than that of patients with no detected chromosomal abnormalities; this difference was observed in overall survival (OS) (P = 0.001) and progression-free survival (PFS) [24 months vs. not reach (NR); P = 0.008]. The patients with multiple chromosomal abnormalities detected by SNP-A had an inferior prognosis, and SNP-A abnormalities (≥3 per patient) were found to be an independent predictor of poor prognosis in patients with MDSs [hazard ratio (HR) = 2.40, P = 0.002]. (3) Patients with ICUS may progress to myeloid malignancies, but most patients often maintain a stable ICUS status for many years without progression. An ICUS patient found to have an MDS-related karyotype would be rediagnosed with MDS. SNP-A can efficiently detect chromosomal abnormalities, which would be important for assessing the evolution of ICUS. In our study, 17 ICUS patients with SNP-A-detected abnormalities developed typical MDSs. Conclusions: SNP-A can help evaluate the prognosis of patients with MDSs and better assess the risk of disease progression for patients with ICUS.

Project description:BackgroundVarious features extracted from breast MRI have the potential to serve as noninvasive biomarkers for the prediction of the biologic behavior of breast cancer. The purpose of this study was to investigate the value of focal breast edema and breast edema score (BES) on T2-weighted images in providing valuable biological information for breast cancer patients' personalized treatment.MethodTwo hundred and five lesions in 201 patients with invasive breast cancer confirmed by surgery or biopsy in Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine from November 2018 to October 2019 were retrospectively recruited and analyzed in this study. Focal edema and BES were evaluated at fat-suppressed T2 weighted imaging. All the lesions were divided into two groups according to the presence of focal edema. The differences in clinicopathological characteristics between the two groups and between different BES were compared.ResultsTwo hundred and five lesions in 201 patients with invasive breast cancer were retrospectively recruited and analyzed in this study. On the fat-suppressed T2WI, focal edema was detected in 102 of 205 lesions (49.8%). BES was positively correlated with tumor size (p < 0.001), histologic grade (p = 0.006), Ki-67 index (p < 0.001), and N stage (p = 0.007), and was negatively correlated with expression of ER and PR (p < 0.001). Higher BES was more likely to present in patients with non-luminal breast cancer (p < 0.001) and suggested the possibility of a higher N stage.ConclusionsFocal edema on T2WI of breast MRI indicates stronger tumor invasiveness, in which non-luminal breast cancer is more inclined to present focal edema. Breast edema score, a novel and practical tool, helps guide the individualized treatment of patients with invasive breast cancer.Critical relevance statementFocal edema on T2WI of breast MRI indicates stronger tumor invasiveness. Breast edema score helps guide the individualized treatment of patients with invasive breast cancer.

Dataset Information

Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information.

Publications

Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information.

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