RNA sequencing validation of the Complexity INdex in SARComas prognostic signature

Lesluyes, Tom; Pérot, Gaëlle; Largeau, Marine R.; Brulard, Céline; Lagarde, Pauline; Dapremont, Valérie; Lucchesi, Carlo; Neuville, Agnès; Terrier, Philippe; Vince-Ranchère, Dominique; Méndez-Lago, María; Gut, Marta; Coindre, Jean‐Michel; Chibon, Fréderic

doi:10.1016/j.ejca.2015.12.027

Cited by 67 publications

(88 citation statements)

References 18 publications

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“…Across different tumors, PD-L1 mRNA level correlated with the copy number of its gene ( CD274 ) (r=0.42, adjusted p=4e–10), but not with PD-1 score. Immune signatures in each sarcoma type were validated using publically available RNA-seq data from 113 sarcomas (Lesluyes et al, 2016). Median immune signatures in LMS, MFS, and SS were strongly correlated between the two studies (Spearman coefficients 0.908, p=8e–09; 0.819, p=9e-06; and 0.858, p=4e-08, respectively) (Figure S7B).…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Abeshouse¹,

Adebamowo²,

Adebamowo³

et al. 2017

Cell

789

568

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SUMMARY Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: 1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types, 2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome, and 3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

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Section: Resultsmentioning

confidence: 99%

“…In order to validate the sarcoma-specific immune infiltration scores identified in our cohort, we repeated our analysis using RNA-seq data from a publically available dataset including 42 UPS, 36 LMS, 18 DDLPS, 15 MFS, and 2 SS (Lesluyes et al, 2016). Only fresh frozen tissue samples were included in the analysis.…”

Section: Star Methodsmentioning

confidence: 99%

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Abeshouse¹,

Adebamowo²,

Adebamowo³

et al. 2017

Cell

789

568

View full text Add to dashboard Cite

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“…These results are highly consistent with the CINSARC signature (Complexity INdex in SARComas) predictive of metastasis free survival. Many of the genes identified encode for proteins involved in cell cycle/mitosis, cytokinesis, mitotic checkpoint, and DNA damage repair (34, 35). …”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma

et al. 2018

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Overall survival of patients with osteosarcoma (OS) has improved little in the past three decades and better models for study are needed. OS is common in large dog breeds and is genetically inducible in mice, making the disease ideal for comparative genomic analyses across species. Understanding the level of conservation of inter-tumor transcriptional variation across species and how it is associated with progression to metastasis will enable us to more efficiently develop effective strategies to manage OS and improve therapy. In this study, transcriptional profiles of OS tumors and cell lines derived from humans (n=49), mice (n=103) and dogs (n=34) were generated using RNA-sequencing. Conserved inter- tumor transcriptional variation was present in tumor sets from all three species and comprised gene clusters associated with cell cycle and mitosis and with the presence or absence of immune cells. Further, we developed a novel Gene Cluster Expression Summary Score (GCESS) to quantify inter-tumor transcriptional variation and demonstrated that these GCESS values associated with patient outcome. Human OS tumors with GCESS values suggesting decreased immune cell presence were associated with metastasis and poor survival. We validated these results in an independent human OS tumor cohort and in 15 different tumor data sets obtained from The Cancer Genome Atlas (TCGA). Our results suggest that quantification of immune cell absence and tumor cell proliferation may better inform therapeutic decisions and improve overall survival for OS patients.

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“…Separately the maximum orthologous probesets per gene symbol were compared cross species resulting in 13,267 log 2 ratios of angiosarcoma to quadriceps (mouse) and angiosarcoma to skeletal muscle (human) STATA/MP 14.1. We compared mouse angiosarcomas to a panel of human soft tissue sarcomas, including angiosarcoma (20), fusion-negative and fusion-positive RMS (21), Ewing Sarcoma (GSE37371), osteosarcoma (22), dedifferentiated liposarcoma, differentiated liposarcoma, leiomyosarcoma, myxofibrosarcoma, and undifferentiated sarcoma (GSE71121)(23). Again the mouse and human probesets were de-duplicated with respect to gene, only the highest for each probeset was retained for each gene.…”

Section: Methodsmentioning

confidence: 99%

Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma

et al. 2017

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Angiosarcoma is an aggressive vascular sarcoma with an extremely poor prognosis. Due to the relative rarity of this disease, its molecular drivers and optimal treatment strategies are obscure. DICER1 is an RNase III endoribonuclease central to microRNA biogenesis, and germline DICER1 mutations result in a cancer predisposition syndrome, associated with an increased risk of many tumor types. Here we show that biallelic Dicer1 deletion with aP2-Cre drives aggressive and metastatic angiosarcoma independent of other genetically engineered oncogenes or tumor suppressor loss. Angiosarcomas in aP2-Cre;Dicer1Flox/−mice histologically and genetically resemble human angiosarcoma. MicroRNA-23 target genes including the oncogenes Ccnd1 as well as Adam19, Plau, and Wsb1 that promote invasiveness and metastasis were enriched in mouse and human angiosarcoma. These studies illustrate that Dicer1 can function as a traditional loss-of-function tumor suppressor gene, and they provide a fully penetrant animal model for the study of angiosarcoma development and metastasis.

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RNA sequencing validation of the Complexity INdex in SARComas prognostic signature

Cited by 67 publications

References 18 publications

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma

Biallelic Dicer1 Loss Mediated by aP2-Cre Drives Angiosarcoma

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