bims-myxlip 2022-04-17 papers

Issue of 2022–04–17
three papers selected by
Laura Mannarino, Humanitas Research

Cancers (Basel). 2022 Mar 30. pii: 1762. [Epub ahead of print]14(7):

miR-214-3p Is Commonly Downregulated by EWS-FLI1 and by CD99 and Its Restoration Limits Ewing Sarcoma Aggressiveness.

Alessandra De Feo, Laura Pazzaglia, Lisa Ciuffarin, Fabio Mangiagli, Michela Pasello, Elisa Simonetti, Evelin Pellegrini, Cristina Ferrari, Giuseppe Bianchi, Benedetta Spazzoli, Katia Scotlandi.

Ewing's sarcoma (EWS), an aggressive pediatric bone and soft-tissue sarcoma, has a very stable genome with very few genetic alterations. Unlike in most cancers, the progression of EWS appears to depend on epigenetic alterations. EWS-FLI1 and CD99, the two hallmarks of EWS, are reported to severely impact the malignancy of EWS cells, at least partly by regulating the expression of several types of non-coding RNAs. Here, we identify miR-214-3p as a common mediator of either EWS-FLI1 or CD99 by in silico analysis. MiR-214-3p expression was lower in EWS cells and in clinical samples than in bone marrow mesenchymal stem cells, and this miRNA was barely expressed in metastatic lesions. Silencing of EWS-FLI1 or CD99 restored the expression of miR-214-3p, leading to a reduced cell growth and migration. Mechanistically, miR-214-3p restoration inhibits the expression of the high-mobility group AT-hook 1 (HMGA1) protein, a validated target of miR-214-3p and a major regulator of the transcriptional machinery. The decrease in HMGA1 expression reduced the growth and the migration of EWS cells. Taken together, our results support that the miR-214-3p is constitutively repressed by both EWS-FLI1 and CD99 because it acts as an oncosuppressor limiting the dissemination of EWS cells.

Keywords: CD99; EWS-FLI1; Ewing sarcoma; HMGA1; miR-214-3p; migration

DOI: https://doi.org/10.3390/cancers14071762

Transl Cancer Res. 2022 Mar;11(3): 488-499

Molecular profiling of gene fusions in soft tissue sarcomas by Ion AmpliSeqTM: a study of 35 cases.

Rong Wei, Feng Gao, Zixin Zeng, Ziwei Gui, Yangwei Shang, Ningning Shen, Ziyue Wang, Weixia Han, Honghong Shen, Xin Li, Li E, Wenxia Ma, Chen Wang.

Background: The accurate diagnosis of sarcoma can be difficult as there are over 70 different subtypes. While molecular profiling in soft tissue sarcoma (STS) has gradually been incorporated into routine diagnostics, conventional methods such as fluorescence in situ hybridization (FISH), reverse transcriptase-PCR (RT-PCR), and Sanger sequencing have several drawbacks. By allowing simultaneous analysis of multiple targets and increasing sequencing depth to achieve ultra-sensitivity, next-generation sequencing (NGS) can not only detect common genetic abnormalities without prior assumptions but also identify uncommon or even new variants.
Methods: In this study, the applicability of NGS in assessing STS using the Ion Torrent Proton was evaluated and compared with other methods. A cohort of 35 tissue specimens from STS patients, including alveolar soft-part sarcoma (ASPS), Ewing's sarcoma (ES), synovial sarcoma (SS), dermatofibrosarcoma protuberans (DFSP), and myxoid liposarcoma (MLPS) patients, were subjected to NGS by an Ion AmpliSeqTM Custom panel.
Results: A proportion of 97.14% (34/35) were successfully conducted to detect gene fusion positive events and met all criteria for good quality. The concordance between NGS and conventional techniques was 94.12% (32/34). NGS also showed superior results, as Sanger sequencing and FISH in two cases were false negatives, demonstrating the excellent diagnostic utility of NGS for translocation detection in STS.
Conclusions: The results in this study show the potential for NGS to aid in diagnosis and clinical monitoring of STS and warrant additional studies in larger cohorts.

Keywords: Soft tissue sarcoma (STS); fluorescence in situ hybridization (FISH); gene fusion; molecular profiling; next generation sequencing

DOI: https://doi.org/10.21037/tcr-22-70

Expert Rev Anticancer Ther. 2022 Apr 12.

Immunotherapy in soft tissue sarcoma: current evidence and future perspectives in a variegated family of different tumour.

Giacomo G Baldi, Alessandro Gronchi, Marcella Tazzari, Silvia Stacchiotti.

INTRODUCTION: In the last few years steps forward in the knowledge of the biology of soft tissue sarcomas (STS) has led to the development of new therapeutic strategies, including immunotherapy.
AREAS COVERED: This review outlines the recent findings on immunological features and provides a synopsis of the results of clinical trials with different immunotherapy approaches in STS, discussing criticisms and how the efficacy of immunotherapy could be improved.
EXPERT OPINION: The heterogeneity of STS has limited generalized approaches of immunotherapy in the disease. Clinical decisions should encompass a comprehensive characterization of the tumour microenvironment (TME), marked by intra-histotype diversity. Profiling of immune cells, checkpoint molecules and antigen target/HLA expression is deemed to re-shape the classical histotype classification for a selection of the most appropriate immune-based treatment. In a synergistic view, tumour-directed treatments, designed on the genetic and epigenetic histotype make-up, should be monitored for their immunomodulant effect and applied to ensure or amplify immunotherapy response. In light of the dynamic nature of the TME, this immunomonitoring should be conducted at baseline and during treatment, for improved therapeutic decisions and rational sequence of treatment combination, pursuing an immunological marker approach by histotype guidance.

Keywords: PD1/PDL1; adoptive cell therapy; advanced disease; histotypes; immune checkpoint inhibitors; immunotherapy; soft tissue sarcoma; tumour microenvironment

DOI: https://doi.org/10.1080/14737140.2022.2065986