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FN1 binds ACVR2A. 30 / 30
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"Aberrant FN1-ACVR2A gene fusion and recurrent ACVR2A mutations also warrant small-molecular inhibitors targeting activin receptor kinases ( xref ) as potential therapeutic modalities against a subset of chondrosarcoma."
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"One case was excluded based on the histological features and the presence of a FN1::ACVR2A fusion—this tumor was reclassified as a secondary CSA arising from synovial chondromatosis."
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"In pathological diagnosis, the gene fusion of FN1-ACVR2A and the overexpression of C-erbB-2 protein can indicate the clonal proliferation characteristics of PSC ( xref , xref )."
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"Compared with SSC, PSC carries a higher risk of malignant transformation, and gene fusions such as FN1-ACVR2A and chromosomal abnormalities have been detected in certain cases ( xref )."
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"Among these, two ( ACVR2A-FN1 and FN1-ACVR2A ) were expressed and validated in the synovial CS6T case ( xref ; Supplemental Fig. S11)."
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"This suggests that promoter activity of the FN1 gene conferred increased FN1-ACVR2A transcript in the tumor."
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"RNA sequencing further revealed that expression of the ACVR2A gene increased more than 25-fold in the FN1-ACVR2A fusion-positive case (CS6T) compared with that of other samples (CS1T and CS7T) (Supplemental Table S10)."
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"Remarkably we found no difference in the histological appearance between synovial chondromatosis with and without FN1-ACVR2A rearrangements."
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"FN1-ACVR2A gene fusions have been recently identified in synovial chondromatosis. xref , xref It was first reported by Totoki et al. xref who investigated chondrosarcomas by whole genome sequencing and found a single case of synovial chondrosarcoma with an FN1 - ACVR2A gene fusion."
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"Four additional cases were tested by whole transcriptome sequencing, showing an FN1-ACVR2A transcript in all cases, including 3 synovial chondromatosis and 1 synovial chondrosarcoma."
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"Moreover, our results showed that 56% (15 of 27) of the cases were positive for FN1-ACVR2A fusion, significantly higher than the 19% reported by Amary et al. None of the cases in our study showed only ACVR2A gene rearrangement with no FN1 gene rearrangement."
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"However, it is not possible to state which of these structurally altered genes drives tumour progression as both FN1-ACVR2A and ACVR2A-FN1 are predicted to be in-frame."
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"This same mechanism may explain the action of the FN1-ACVR2A fusion, namely that FN1 may facilitate dimerisation of ACVR2A inducing activin signaling."
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"The true prevalence of cases harbouring these alterations is likely to be higher on the basis that only one of three synovial chondroma/chondromatosis cases that revealed a FN1-ACVR2A fusion gene by RNA sequencing demonstrated break-apart signals involving both genes."
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"The high incidence of FN1-ACVR2A gene fusions in synovial osteochondromatosis is reported [ xref , xref ]."
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"The presence of a FN1-ACVR2 fusion did not distinguish between benign and malignant disease, but we showed that copy number alteration of CDKN2A appears to be a valuable predictor of malignancy, similarly to conventional cartilaginous tumours ( xref , xref ) where copy number alterations of CDKN2A appear exclusively in chondrosarcomas."
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"Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases."
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"However, analysis of a synovial subtype identified recurrent FN1-ACVR2A fusion transcript, which further suggests a molecular link between chondrosarcoma and osteochondromatosis."
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"RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%."
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"The recent findings of FN1-ACVR2A and ACVR2A-FN1 in-frame fusions in a case of chondrosarcoma arising secondary to synovial chondromatosis and in one of seven cases of synovial chondromatosis ( xref ), indicate that these lesions represent neoplasms, and that they rarely transform into secondary chondrosarcoma ( xref – xref )."
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"Results showed that FN1 and /or ACVR2A gene rearrangements were noted in 18 cases (67%), with an FN1-ACVR2A fusion being confirmed in 15 (56%) cases."
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"Studies using cell proliferation assays have differed on the extent of DNA aneuploidy seen in synovial chondromatosis. xref , xref An FN1-ACVR2A in-frame gene fusion was initially identified in one case each of synovial osteochondromatosis and synovial chondrosarcoma, during a genomic investigation of various benign and malignant cartilaginous neoplasms. xref In a more recent study, Amary et al. further confirmed these findings using FISH analysis and whole-transcriptome RNA sequencing on a large number of cases, showing that 57% of synovial chondromatosis harbored FN1 and/or ACVR2A gene rearrangements. xref Of the 7 synovial chondrosarcomas included in their study, only 4 were informative by FISH, showing evidence of FN1 and/or the ACVR2A gene rearrangements in 3 cases. xref "
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"In this study we investigate a large cohort of synovial chondromatosis for the prevalence of the FN1-ACVR2A fusion."
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"As this lesion harbored a previously unreported gene fusion, we attempted to establish its recurrent potential vis-à-vis the more common FN1-ACVR2A fusion."
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"FN1-ACVR2A gene fusion seen in 67% of synovial chondromatosis."
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"This biomarker has considerable clinical value: In terms of diagnosis, the sensitivity of FN1-ACVR2A fusion for identifying SS is 92%, and the specificity is 100% ( xref ); in terms of prognosis, patients with positive fusion have a 2.3-fold increased risk of recurrence, and the overexpression of C-erbB-2 is negatively associated with chemotherapy response ( xref )."
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"Although FN1-ACVR2A has not been included in the diagnostic criteria for malignancy, its status should be noted in the pathological report and integrated with imaging and clinical manifestations for risk-stratification management ( xref )."
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"K36M) ( xref ), mesenchymal chondrosarcoma is characterized by the fusion of HEY1-NCOA2 ( xref ), chondromyxoid fibroma is characterized by GRM1 rearrangements ( xref ), aneurysmal bone cyst is characterized by USP6 rearrangements ( xref ), osteoblastoma/osteoid osteoma is characterized by FOS/FOSB rearrangements ( xref ), and synovial chondromatosis is characterized by the fusion of FN1-ACVR2A and ACVR2A-FN1 ( xref )."
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"Both these entities are characterized by FN1-ACVR2A and ACVR2A-FN1 fusions [ xref ], which are present in at least 50% of synovial chondromatosis."
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"To analyse further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCRA2 gene rearrangements do not distinguish between benign and malignant synovial chondromatosis."
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