Dataset Information

RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas.

ABSTRACT: Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these sarcomas. Despite genetic heterogeneity across samples, oncogenesis may be driven by common pathway alterations. Therefore, genomic and transcriptomic profiles of 106 sarcomas with complex genomics were analyzed to identify common pathways with altered genes. This brought out a gene belonging to the "cell cycle" biological pathway, RCBTB1 (RCC1 And BTB Domain Containing Protein 1), which is lost and downregulated in 62.5% of metastatic tumors against 34% of non-metastatic tumors. A retrospective study of three sarcoma cohorts revealed that low RCBTB1 expression is prognostic for metastatic progression, specifically in patients that received chemotherapy. In vitro and in vivo, RCBTB1 overexpression in leiomyosarcoma cells specifically sensitized to docetaxel-induced apoptosis. This was associated with increased mitotic rate in vitro and higher growth rate of xenografts. By contrast, RCBTB1 inhibition decreased cell proliferation and protected sarcoma cells from apoptosis induced by docetaxel. Collectively, these data evidenced that RCBTB1 is frequently deleted in sarcomas with complex genomics and that its downregulation is associated with a higher risk of developing metastasis for patients receiving chemotherapy, likely due to their higher resistance to docetaxel.

SUBMITTER: Mauduit O

PROVIDER: S-EPMC6356223 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas.

Mauduit Olivier O Brulard Céline C Lesluyes Tom T Delcroix Vanessa V Pérot Gaëlle G Choublier Nina N Michaud Mickael M Baud Jessica J Lagarde Pauline P Aurias Alain A Coindre Jean-Michel JM Lartigue Lydia L Blay Jean-Yves JY Chibon Frédéric F

Cancers 20190111 1

Half of soft-tissue sarcomas are tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these sarcomas. Despite genetic heterogeneity across samples, oncogenesis may be driven by common pathway alterations. Therefore, genomic and transcriptomic profiles of 106 sarcomas with complex genomics were analyzed to identify common pathways with altered genes. This brought out a gene belong ...[more]

PMID: 30641971

Similar Datasets

Project description:BackgroundUndifferentiated pleomorphic sarcoma (UPS) is the most frequent, aggressive and less-characterized sarcoma subtype. This study aims to assess UPS molecular characteristics and identify specific therapeutic targets.MethodsHigh-throughput technologies encompassing immunohistochemistry, RNA-sequencing, whole exome-sequencing, mass spectrometry, as well as radiomics were used to characterize three independent cohorts of 110, 25 and 41 UPS selected after histological review performed by an expert pathologist. Correlations were made with clinical outcome. Cell lines and xenografts were derived from human samples for functional experiments.FindingsCD8 positive cell density was independently associated with metastatic behavior and prognosis. RNA-sequencing identified two main groups: the group A, enriched in genes involved in development and stemness, including FGFR2, and the group B, strongly enriched in genes involved in immunity. Immune infiltrate patterns on tumor samples were highly predictive of gene expression classification, leading to call the group B 'immune-high' and the group A 'immune-low'. This molecular classification and its prognostic impact were confirmed on an independent cohort of UPS from TCGA. Copy numbers alterations were significantly more frequent in immune-low UPS. Proteomic analysis identified two main proteomic groups that highly correlated with the two main transcriptomic groups. A set of nine radiomic features from conventional MRI sequences provided the basis for a radiomics signature that could select immune-high UPS on their pre-therapeutic imaging. Finally, in vitro and in vivo anti-tumor activity of FGFR inhibitor JNJ-42756493 was selectively shown in cell lines and patient-derived xenograft models derived from immune-low UPS.InterpretationTwo main disease entities of UPS, with distinct immune phenotypes, prognosis, molecular features and MRI textures, as well as differential sensitivity to specific anticancer agents were identified. Immune-high UPS may be the best candidates for immune checkpoint inhibitors, whereas this study provides rational for assessing FGFR inhibition in immune-low UPS.FundingThis work was partly founded by a grant from La Ligue.

Dataset Information

RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas.

Publications

RCBTB1 Deletion Is Associated with Metastatic Outcome and Contributes to Docetaxel Resistance in Nontranslocation-Related Pleomorphic Sarcomas.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets