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WGS Leiomyosarcoma subtypes

ABSTRACT: Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

PROVIDER: EGAS00001005341 | EGA |

REPOSITORIES: EGA

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Rna-Seq Leiomyosarcoma subtypes

Project description:Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyzed 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlighted the extremely early origins of LMS. Three specific subtypes of LMS develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynaecological origin acquired the highest burden of genomic mutation and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP and other DNA damage response inhibitors, suggesting a novel therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

| EGAS00001004783 | EGA

Profiling of three leiomyosarcoma molecular subtypes with RNA-sequencing

Project description:Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation, and there are three molecular subtypes of LMS which have been defined previously by our lab. To further validate these subtypes and identify potential therapeutic targets in each subtype, we profiled the LMS cases from each subtype with RNA-Seq technology.

2015-12-25 | GSE62544 | GEO

Stratification of Leiomyosarcoma molecular subtypes by 3' end RNA-sequencing: Toward precision medicine

2015-05-19 | GSE45510 | GEO

Different molecular pathways along with pathogenesis of three subtypes of Leiomyosarcoma

2015-05-19 | GSE54511 | GEO

Different molecular pathways along with pathogenesis of three subtypes of Leiomyosarcoma

Project description:Leiomyosarcoma (LMS) is a malignant neoplasm of smooth muscle and is an aggressive soft tissue tumor, have complex genetic abnormalities and could be defined as three molecular subtypes. Since that the molecular heterogeneity of LMS, the pathogenesis analysis per subtype will be highly necessary and helpful to understand the etiology of this more common sarcoma. Within this study, we collected four Myometrium, three Leiomyoma, three LMS cell lines and 99 LMSs (GSE45510), performed the system-wide gene expression profiling by 3'end RNA Sequencing, and found that there are significant different molecular pathways along the pathogenesis for those three molecular subtypes.

2015-05-19 | E-GEOD-54511 | biostudies-arrayexpress

Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency

Project description:Leiomyosarcoma (LMS) is an aggressive cancer with few therapeutic options. LMS cells are more sensitive to proteotoxic stress compared to normal smooth muscle cells. We used small compound 2c to induce proteotoxic stress and compare the transcriptomic adaptations of immortalized human uterine smooth muscle cells (HUtSMC) and LMS cells SK-UT-1. We found that the expression of the heat shock proteins (HSP) gene family is upregulated with higher efficiency in normal cells. In contrast, upregulation of BH3-only proteins is higher in LMS cells. HSF1, the master regulator of HSP transcription, is sequestered into transcriptionally incompetent nuclear foci only in LMS cells, which explains the lower HSP upregulation. We also found that several compounds can enhance the cell death response to proteotoxic stress. Specifically, when low doses were used, an inhibitor of salt-inducible kinases (SIKs) and the inhibitor of IRE1, a key element of the unfolded protein response (UPR), support proteotoxic-induced cell death with strength in LMS cells and without effects on the survival of normal cells. Overall, our data provide an explanation for the higher susceptibility of LMS cells to proteotoxic stress and suggest a potential option for co-treatment strategies.

2022-10-03 | GSE205596 | GEO

RNAseq analysis of primary differentiated rat aorta tissue compared to proliferative cultured cells

Project description:Investigation of alternative splicing changes in rat smooth muscle aorta differentiated tissue compared to dedifferentiated proliferative aorta smooth muscle cells in culture.

2019-06-18 | GSE127794 | GEO

Oncogenic gene expression programs in leiomyosarcoma and characterization of conventional, inflammatory and uterogenic subtypes

Project description:Leiomyosarcoma (LMS) is a mesenchymal neoplasm with complex copy number alterations and characteristic loss of tumor suppressor genes without known recurrent activating mutations. Clinical management of advanced LMS relies on chemotherapy and complementary palliative approaches, and research efforts to date have had limited success identifying clinically actionable biomarkers or targeted therapeutic vulnerabilities. To explore the biological underpinning of LMS, we evaluated gene expression patterns of this disease in comparison to diverse sarcomas, non-mesenchymal neoplasms and normal myogenic tissues. We identified a recurrent gene expression program in LMS, with evidence of oncogenic evolution of an underlying smooth muscle lineage-derived program characterized by activation of E2F1 and downstream effectors. Recurrently amplified or highly expressed genes in LMS were identified that may represent therapeutic vulnerabilities, including targeting of IGF1R and retinoid signaling pathways. Though the majority of expressed transcripts were conserved across LMS samples, three separate subtypes were identified that were enriched for muscle-associated transcripts (conventional-LMS), immune markers (inflammatory-LMS) or a uterine-like gene expression program (uterogenic-LMS). Each of these subtypes express a unique subset of genes that may be useful in the managemeny of LMS: IGF1R was enriched in conventional LMS with prognostic implications, worse disease-specific survival was observed in inflammatory LMS, and prolactin was elaborated by uterogenic LMS and may represent a disease biomarker. These results extend our understanding of LMS biology and identify several strategies and challenges for further translational investigation.

2020-06-09 | GSE146360 | GEO

Stratification of Leiomyosarcoma molecular subtypes by 3' end RNA-sequencing: Toward precision medicine

Project description:Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. We demonstrate the existence of 3 molecular subtypes in a cohort of 99 cases and an independent cohort of 82 LMS. Two new FFPE tissue-compatible diagnostic immunohistochemical markers are identified: LMOD1 for subtype I LMS and ARL4C for subtype II LMS. Subtype I and subtype II LMS are associated with good and poor prognosis, respectively. The LMS subtypes show significant differences in expression levels for genes for which novel targeted therapies are being developed. Gene expression profiling was performed by 3' End RNA Sequencing (3SEQ), a next generation sequencing approach that does not rely on frozen tissue but can be performed on archival FFPE tissue. Samples included 99 LMS, 6 Undifferentiated Pleomorphic Sarcomas (UPS), 3 leiomyomas, 4 normal myometrium samples, and 1 case of Lymphangioleiomyomatosis (LAM). This study only includes the 99 LMS Samples. After gene expression levels were quantified by 3SEQ analysis pipeline, Consensus Clustering with bootstrap method was used to determine that the dataset contained three robust subtypes, and Silhouette analysis was performed to validate the subtype assignments. Two class SAM analysis (Significance Analysis of Microarrays) was performed to identify genes expressed differentially between each subtype of LMS with FDR of 0.05. Immunohistochemical staining was used to validate the potential diagnostic and prognostic markers from 3SEQ data on a tissue microarray.

2015-05-19 | E-GEOD-45510 | biostudies-arrayexpress

Undifferentiated pleomorphic sarcoma recapitulates the expressional profile of Subtype II Leiomyosarcoma

Project description:Background: Undifferentiated pleomorphic sarcoma (UPS), used to be called malignant fibrous histiocytoma (MFH), is a malignant soft tissue tumor of uncertain origin, and is characterized by morphology. UPS often share similar morphological characters with other sarcomas, especially Leiomyosarcoma. Leiomyosarcoma (LMS) is another malignant soft tissue sarcoma with complex genomic abnormalities, origin from smooth muscle. As a result, development of gene signature and/or biomarkers distinguishing UPS and LMS will definitely help the pathologist to precisely diagnose those patients. However, in the past, UPS was reported to be indistinguishable with LMS by genomic profiles. Methods and Results: In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. Overall, UPS was undistinguished with LMS by 3SEQ data, however, when we stratified LMS into three subtypes, UPS was shown to share similar expression pattern with Subtype II LMS, but had distinct molecular expression patterns with Subtype I and Subtype III LMS. Additional Immunohistochemistry staining by using LMS Subtype I and Subtype II markers validated that UPSs were positive for Subtype II marker ARL4C, but negative for Subtype I marker LMOD1. Furthermore, CD4 was shown to be significantly more highly expressed in UPS than LMS in both mRNA and protein levels. Conclusion: This study first reported that UPS shared similar gene expression pattern with subtype II LMS and UPS recapitulated the expression profiles of subtype II LMS. In this study, 3’ end RNA Sequencing (3SEQ) was used to expression profile 6 UPS and 99 LMS cases. In order to explore the molecular differences between UPS and LMS, We analyzed the expression data by SAMseq to identify the genes which were significantly differently expressed between UPS and LMS, between UPS and each LMS subtype.

2015-05-19 | E-GEOD-53844 | biostudies-arrayexpress

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