PMID- 31592798 OWN - NLM STAT- MEDLINE DCOM- 20200804 LR - 20211204 IS - 1532-0979 (Electronic) IS - 0147-5185 (Print) IS - 0147-5185 (Linking) VI - 44 IP - 3 DP - 2020 Mar TI - Recurrent YAP1 and KMT2A Gene Rearrangements in a Subset of MUC4-negative Sclerosing Epithelioid Fibrosarcoma. PG - 368-377 LID - 10.1097/PAS.0000000000001382 [doi] AB - Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma, characterized by a distinctive epithelioid phenotype in a densely sclerotic collagenous stroma, that shows frequent MUC4 immunoreactivity and recurrent gene fusions, often involving EWSR1 gene. A pathogenetic link with low-grade fibromyxoid sarcoma (LGFMS) has been suggested, due to cases with hybrid morphology as well as overlapping genetic signature. However, a small subset of SEF is negative for MUC4 and lacks the canonical EWSR1/FUS gene rearrangements. Triggered by the identification of recurrent YAP1-KMT2A gene fusions by RNA sequencing in 3 index cases of MUC4-negative, EWSR1/FUS fusion-negative SEF, we further investigated a cohort of 14 similar SEF cases (MUC4-negative, EWSR1/FUS fusion-negative) by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction, and/or DNA-based massively parallel sequencing (MSK-IMPACT) for abnormalities in these genes. Three additional SEFs with KMT2A gene rearrangements and one additional case with YAP1 gene rearrangements were identified by FISH. In addition, one case with YAP1-KMT2A and one with KMT2A-YAP1 fusion were detected by reverse transcription-polymerase chain reaction and MSK-IMPACT, respectively. As a control group, 24 fibromyxoid spindle cell tumors, diagnosed or suspected as fusion-negative LGFMS, were also tested for YAP1 and KMT2A abnormalities by FISH, but none were positive. The YAP1/KMT2A-rearranged SEF group affected patients ranging from 10 to 86 years old (average and median: 45) of both sexes (4 females, 5 males). The tumors involved somatic soft tissues with a wide distribution, including extremities, trunk, neck, and dura. Histologically, the tumors showed variable cellularity, with monotonous ovoid to epithelioid tumor cells and hyalinized collagenous background typical of SEF. More than half of the cases showed infiltrative borders, within fat or skeletal muscle. No LGFMS component was identified. All tumors were negative for MUC4 and had an otherwise nonspecific immunophenotype. Of the 6 cases with available follow-up information, 2 had local recurrences, and 2 developed soft tissue and/or bone metastases, including 1 of them died of the disease. FAU - Kao, Yu-Chien AU - Kao YC AD - Department of Pathology, Shuang Ho Hospital, Taipei Medical University. AD - Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University. FAU - Lee, Jen-Chieh AU - Lee JC AD - Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei. FAU - Zhang, Lei AU - Zhang L AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Sung, Yun-Shao AU - Sung YS AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Swanson, David AU - Swanson D AD - Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada. FAU - Hsieh, Tsung-Han AU - Hsieh TH AD - Joint Biobank, Office of Human Research, Taipei Medical University. FAU - Liu, Yun-Ru AU - Liu YR AD - Joint Biobank, Office of Human Research, Taipei Medical University. FAU - Agaram, Narasimhan P AU - Agaram NP AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. FAU - Huang, Hsuan-Ying AU - Huang HY AD - Department of Anatomical Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. FAU - Dickson, Brendan C AU - Dickson BC AD - Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada. FAU - Antonescu, Cristina R AU - Antonescu CR AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P50 CA140146/CA/NCI NIH HHS/United States GR - P50 CA217694/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Am J Surg Pathol JT - The American journal of surgical pathology JID - 7707904 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Biomarkers, Tumor) RN - 0 (KMT2A protein, human) RN - 0 (MUC4 protein, human) RN - 0 (Mucin-4) RN - 0 (Transcription Factors) RN - 0 (YAP-Signaling Proteins) RN - 0 (YAP1 protein, human) RN - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein) RN - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase) SB - IM MH - Adaptor Proteins, Signal Transducing/*genetics MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers, Tumor/*genetics/metabolism MH - Case-Control Studies MH - Child MH - Female MH - Fibrosarcoma/diagnosis/*genetics/pathology MH - Follow-Up Studies MH - Gene Fusion MH - *Gene Rearrangement MH - High-Throughput Nucleotide Sequencing MH - Histone-Lysine N-Methyltransferase/*genetics MH - Humans MH - In Situ Hybridization, Fluorescence MH - Male MH - Middle Aged MH - Mucin-4/*metabolism MH - Myeloid-Lymphoid Leukemia Protein/*genetics MH - Reverse Transcriptase Polymerase Chain Reaction MH - Soft Tissue Neoplasms/diagnosis/*genetics/pathology MH - Transcription Factors/*genetics MH - YAP-Signaling Proteins MH - Young Adult PMC - PMC7012758 MID - NIHMS1539509 EDAT- 2019/10/09 06:00 MHDA- 2020/08/05 06:00 PMCR- 2021/03/01 CRDT- 2019/10/09 06:00 PHST- 2019/10/09 06:00 [pubmed] PHST- 2020/08/05 06:00 [medline] PHST- 2019/10/09 06:00 [entrez] PHST- 2021/03/01 00:00 [pmc-release] AID - 00000478-202003000-00008 [pii] AID - 10.1097/PAS.0000000000001382 [doi] PST - ppublish SO - Am J Surg Pathol. 2020 Mar;44(3):368-377. doi: 10.1097/PAS.0000000000001382.