PMID- 34504309
OWN - NLM
STAT- MEDLINE
DCOM- 20220404
LR  - 20230210
IS  - 1530-0285 (Electronic)
IS  - 0893-3952 (Linking)
VI  - 35
IP  - 2
DP  - 2022 Feb
TI  - Identification of novel SSX1 fusions in synovial sarcoma.
PG  - 228-239
LID - 10.1038/s41379-021-00910-x [doi]
AB  - Synovial sarcoma is characterized by variable epithelial differentiation and 
      specific SS18-SSX gene fusions. The diagnosis is primarily based on phenotype, 
      but fusion gene detection is increasingly being considered indispensable, with 
      SS18 break-apart fluorescence in situ hybridization (FISH) being favored in many 
      laboratories. However, SS18 FISH assay produces negative or atypical results in a 
      minority of cases, leaving uncertainties in diagnosis and management. Here, we 
      analyzed this challenging subset of SS18 FISH-negative/atypical synovial sarcoma 
      using RNA sequencing and monoclonal antibodies that recognize SS18-SSX and the 
      SSX C-terminus. Among 99 synovial sarcoma cases that were previously subjected to 
      SS18 break-apart FISH, eight cases were reported as negative and three cases were 
      indeterminate, owing to atypical signal patterns. Three of these 11 tumors (two 
      monophasic and one biphasic) harbored novel EWSR1-SSX1 fusions, were negative for 
      SS18-SSX staining, and were positive for SSX C-terminus staining. One monophasic 
      tumor harbored a novel MN1-SSX1 fusion, and showed negative SS18-SSX expression 
      and positive SSX C-terminus staining. Another monophasic tumor carried an 
      SS18L1-SSX1 fusion, and was weakly positive for SS18-SSX, while SMARCB1 
      expression was reduced. The presence of these novel and/or rare fusions was 
      confirmed using RT-PCR and Sanger sequencing. EWSR1-SSX1 was further validated by 
      EWSR1 FISH assay. The remaining six tumors (five monophasic and one biphasic) 
      showed strong SS18-SSX expression, and RNA sequencing successfully performed in 
      three cases identified canonical SS18-SSX2 fusions. Based on a DNA 
      methylation-based unsupervised clustering, the tumors with EWSR1-SSX1 and 
      SS18L1-SSX1 clustered with synovial sarcoma, while the MN1-SSX1-positive tumor 
      was not co-clustered despite classic histology and immunoprofile. In summary, we 
      discovered novel and rare SSX1 fusions to non-SS18 genes in synovial sarcoma. The 
      expanded genetic landscape carries significant diagnostic implications and 
      advances our understanding of the oncogenic mechanism.
CI  - (c) 2021. The Author(s), under exclusive licence to United States & Canadian 
      Academy of Pathology.
FAU - Yoshida, Akihiko
AU  - Yoshida A
AUID- ORCID: 0000-0002-3373-0099
AD  - Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 
      Japan. akyoshid@ncc.go.jp.
AD  - Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan. 
      akyoshid@ncc.go.jp.
FAU - Arai, Yasuhito
AU  - Arai Y
AUID- ORCID: 0000-0001-6306-9409
AD  - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, 
      Japan.
FAU - Satomi, Kaishi
AU  - Satomi K
AUID- ORCID: 0000-0001-7611-5822
AD  - Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 
      Japan.
FAU - Kubo, Takashi
AU  - Kubo T
AD  - Department of Laboratory Medicine, National Cancer Center Hospital, Tokyo, Japan.
AD  - Department of Clinical Genomics, National Cancer Center Research Institute, 
      Tokyo, Japan.
FAU - Ryo, Eijitsu
AU  - Ryo E
AD  - Division of Molecular Pathology, National Cancer Center Research Institute, 
      Tokyo, Japan.
FAU - Matsushita, Yuko
AU  - Matsushita Y
AD  - Division of Brain Tumor Translational Research, National Cancer Center Research 
      Institute, Tokyo, Japan.
AD  - Department of Brain Disease Translational Research, Juntendo University Faculty 
      of Medicine, Tokyo, Japan.
FAU - Hama, Natsuko
AU  - Hama N
AD  - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, 
      Japan.
FAU - Sudo, Kazuki
AU  - Sudo K
AD  - Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.
AD  - Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Komiyama, Motokiyo
AU  - Komiyama M
AD  - Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.
AD  - Department of Urology, National Cancer Center Hospital, Tokyo, Japan.
FAU - Yatabe, Yasushi
AU  - Yatabe Y
AUID- ORCID: 0000-0003-1788-559X
AD  - Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 
      Japan.
AD  - Division of Molecular Pathology, National Cancer Center Research Institute, 
      Tokyo, Japan.
FAU - Shibata, Tatsuhiro
AU  - Shibata T
AD  - Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, 
      Japan.
FAU - Ichikawa, Hitoshi
AU  - Ichikawa H
AUID- ORCID: 0000-0003-0142-2240
AD  - Department of Clinical Genomics, National Cancer Center Research Institute, 
      Tokyo, Japan.
AD  - Division of Translational Genomics, Exploratory Oncology Research and Clinical 
      Trial Center, National Cancer Center, Tokyo, Japan.
FAU - Ichimura, Koichi
AU  - Ichimura K
AUID- ORCID: 0000-0002-3851-2349
AD  - Division of Brain Tumor Translational Research, National Cancer Center Research 
      Institute, Tokyo, Japan.
AD  - Department of Brain Disease Translational Research, Juntendo University Faculty 
      of Medicine, Tokyo, Japan.
FAU - Kawai, Akira
AU  - Kawai A
AD  - Rare Cancer Center, National Cancer Center Hospital, Tokyo, Japan.
AD  - Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, 
      Japan.
FAU - Mori, Taisuke
AU  - Mori T
AUID- ORCID: 0000-0003-1838-7883
AD  - Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, 
      Japan.
AD  - Division of Molecular Pathology, National Cancer Center Research Institute, 
      Tokyo, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210909
PL  - United States
TA  - Mod Pathol
JT  - Modern pathology : an official journal of the United States and Canadian Academy 
      of Pathology, Inc
JID - 8806605
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Repressor Proteins)
SB  - IM
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Oncogene Proteins, Fusion/genetics/metabolism
MH  - Proto-Oncogene Proteins/genetics
MH  - Repressor Proteins/genetics
MH  - *Sarcoma, Synovial/pathology
EDAT- 2021/09/11 06:00
MHDA- 2022/04/05 06:00
CRDT- 2021/09/10 06:54
PHST- 2021/06/13 00:00 [received]
PHST- 2021/08/15 00:00 [accepted]
PHST- 2021/08/13 00:00 [revised]
PHST- 2021/09/11 06:00 [pubmed]
PHST- 2022/04/05 06:00 [medline]
PHST- 2021/09/10 06:54 [entrez]
AID - S0893-3952(22)00334-9 [pii]
AID - 10.1038/s41379-021-00910-x [doi]
PST - ppublish
SO  - Mod Pathol. 2022 Feb;35(2):228-239. doi: 10.1038/s41379-021-00910-x. Epub 2021 
      Sep 9.