Complexity index in sarcoma and genomic grade index gene signatures in rhabdomyosarcoma of pediatric and adult ages
Andrea Ferrari
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorMaria Federica Iannó
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorCorresponding Author
Andrea Carenzo
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Correspondence
Patrizia Gasparini, Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Andrea Carenzo, Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Email: [email protected]; [email protected]
Search for more papers by this authorOrazio Fortunato
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Search for more papers by this authorMichela Casanova
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorStefano Chiaravalli
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorLuca Bergamaschi
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorRossella Bertulli
Adult Mesenchymal Tumor and Rare Cancer Medical Oncology Unit, Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, , Milan, 20133 Italy
Search for more papers by this authorFrancesca Cattaneo
University of Milano School of Medicine, Milano, Italy
Search for more papers by this authorPaola Collini
Soft Tissue and Bone Pathology, and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorAnnalisa Trama
Evaluative Epidemiology, Fondazione IRCCS Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorGabriella Sozzi
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Search for more papers by this authorMaura Massimino
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorLoris De Cecco
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorCorresponding Author
Patrizia Gasparini
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Correspondence
Patrizia Gasparini, Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Andrea Carenzo, Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Email: [email protected]; [email protected]
Search for more papers by this authorAndrea Ferrari
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorMaria Federica Iannó
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorCorresponding Author
Andrea Carenzo
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Correspondence
Patrizia Gasparini, Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Andrea Carenzo, Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Email: [email protected]; [email protected]
Search for more papers by this authorOrazio Fortunato
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Search for more papers by this authorMichela Casanova
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorStefano Chiaravalli
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorLuca Bergamaschi
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorRossella Bertulli
Adult Mesenchymal Tumor and Rare Cancer Medical Oncology Unit, Medical Oncology and Hematology Department, Fondazione IRCCS Istituto Nazionale Tumori, , Milan, 20133 Italy
Search for more papers by this authorFrancesca Cattaneo
University of Milano School of Medicine, Milano, Italy
Search for more papers by this authorPaola Collini
Soft Tissue and Bone Pathology, and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorAnnalisa Trama
Evaluative Epidemiology, Fondazione IRCCS Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorGabriella Sozzi
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Search for more papers by this authorMaura Massimino
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorLoris De Cecco
Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Search for more papers by this authorCorresponding Author
Patrizia Gasparini
Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 20133 Italy
Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan, 20133 Italy
Correspondence
Patrizia Gasparini, Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Andrea Carenzo, Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy.
Email: [email protected]; [email protected]
Search for more papers by this authorAndrea Ferrari and Maria Federica Iannó contributed equally to this work.
Loris De Cecco and Patrizia Gasparini are co-last authors.
Abstract
Background
Rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma in childhood, shows extensive heterogeneity in histology, site and age of onset, clinical course, and prognosis. Adolescents and young adults (AYA) with RMS form a subgroup of patients whose survival lacks behind that of children while diagnosed with histologically similar tumors.
Procedures
A 67-gene prognostic signature related to chromosome integrity, mitotic control, and genome complexity in sarcomas (CINSARC) is considered a powerful tool for identifying tumors with a highly metastatic potential. With this study, we investigated the prognostic value of CINSARC signature on a cohort of 48 pediatric (PEDs) and AYAs-RMS.
Results
CINSARC resulted not significantly correlated with age, suggesting other determinants to be responsible for that difference in survival. It remained a significant prognostic variable in both the groups of PEDs and AYAs. Also, genomic grade index signature was tested on the same cohort and showed very similar results with CINSARC.
Conclusions
Our study showed that CINSARC correlated with outcome in RMS patients and may be potentially considered a tool to predict outcome, and so stratify RMS patients.
CONFLICTS OF INTEREST
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.
Supporting Information
| Filename | Description |
|---|---|
| pbc28987-sup-0001-FigureS1.pdf15.9 KB | Supporting Information Figure S1: Kaplan-Meier progression-free survival curves for CINSARC. |
| pbc28987-sup-0002-FigureS2.pdf51.9 KB | Supporting Information Figure S2: CINSARC (original method) analysis |
| pbc28987-sup-0003-FigureS3.pdf24.4 KB | Supporting Information Figure S3: Kaplan-Meier survival curves for age class. |
| pbc28987-sup-0004-FigureS4.pdf25.7 KB | Supporting Information Figure S4: Kaplan-Meier survival curves for CINSARC divided by age. |
| pbc28987-sup-0005-FigureS5.pdf32.7 KB | Supporting Information Figure S5: HALLMARK_TNFA_SIGNALING_VIA_NFKB analysis |
| pbc28987-sup-0006-FigureS6.pdf63.7 KB | Supporting Information Figure S6: GGI analysis. |
| pbc28987-sup-0007-TableS1.xlsx25.3 KB | Supporting Information Table S1: Genes and probes composing the CINSARC and GGI signatures. Overlap between CINSARC and GGI, as well as CINSARC original and z-score stratification. |
| pbc28987-sup-0008-TableS2.xlsx36.4 KB | Supporting Information Table S2: GSEA of the Hallmark gene sets with samples divided by risk group and age class. |
| pbc28987-sup-0009-TableS3.xlsx10.6 KB | Supporting Information Table S3: Clinical pathological features of the RMS series stratified by GGI score. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Ferrari A, Brecht IB, Gatta G, et al. Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer. 2019; 110: 120-126.
- 2Ferrari A, Trama A, De PA, et al. Access to clinical trials for adolescents with soft tissue sarcomas: enrollment in European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) protocols. Pediatr Blood Cancer. 2017; 64(6). doi: 10.1002/pbc.26348.
- 3Ferrari A, Dama E, Pession A, et al. Adolescents with cancer in Italy: entry into the national cooperative paediatric oncology group AIEOP trials. Eur J Cancer. 2009; 45(3): 328-334.
- 4Trama A, Botta L, Foschi R, et al. Survival of European adolescents and young adults diagnosed with cancer in 2000-07: population-based data from EUROCARE-5. Lancet Oncol. 2016; 17(7): 896-906.
- 5Gasparini P, Fortunato O, De CL, et al. Age-related alterations in immune contexture are associated with aggressiveness in rhabdomyosarcoma. Cancers (Basel). 2019; 11(9): 1380.
- 6Chibon F, Lagarde P, Salas S, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med. 2010; 16(7): 781-787.
- 7Chibon F, Lesluyes T, Valentin T, Le GS. CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond. Genes Chromosomes Cancer. 2019; 58(2): 124-129.
- 8Chakiba C, Lagarde P, Pissaloux D, et al. Response to chemotherapy is not related to chromosome instability in synovial sarcoma. Ann Oncol. 2014; 25(11): 2267-2271.
- 9Lagarde P, Przybyl J, Brulard C, et al. Chromosome instability accounts for reverse metastatic outcomes of pediatric and adult synovial sarcomas. J Clin Oncol. 2013; 31(5): 608-615.
- 10Lesluyes T, Delespaul L, Coindre JM, Chibon F. The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms. Sci Rep. 2017; 7(1): 5480.
- 11Bertucci F, Finetti P, Ostrowski J, et al. Genomic grade index predicts postoperative clinical outcome of GIST. Br J Cancer. 2012; 107(8): 1433-1441.
- 12Bertucci F, De NA, Finetti P, et al. The genomic grade index predicts postoperative clinical outcome in patients with soft-tissue sarcoma. Ann Oncol. 2018; 29(2): 459-465.
- 13Huber W, Carey VJ, Gentleman R, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods. 2015; 12(2): 115-121.
- 14Carvalho BS, Irizarry RA. A framework for oligonucleotide microarray preprocessing. Bioinformatics. 2010; 26(19): 2363-2367.
- 15Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics. 2013; 14: 7.
- 16Budczies J, Klauschen F, Sinn BV, et al. Cutoff Finder: a comprehensive and straightforward web application enabling rapid biomarker cutoff optimization. PLoS ONE. 2012; 7(12):e51862.
- 17Lesluyes T, Chibon F. A global and integrated analysis of CINSARC-associated genetic defects. Cancer Res. 2020; 80(23): 5282-5290.
- 18 survminer: Drawing Survival Curves using “ggplot2” [computer program]. Version R package version 0.4.6. 2020.
- 19Wickham H, et al. Welcome to the Tidyverse. J Open Source Softw. 2019; 4(43):1686.
10.21105/joss.01686 Google Scholar
- 20Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43): 15545-15550.
- 21Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015; 1(6): 417-425.
- 22Sergushichev AA. An algorithm for fast preranked gene set enrichment analysis using cumulative statistic calculation. bioRxiv. 2016:060012.
- 23Maurer HM, Beltangady M, Gehan EA, et al. The intergroup rhabdomyosarcoma study I. A final report. Cancer. 1988; 61(2): 209-220.
10.1002/1097-0142(19880115)61:2<209::AID-CNCR2820610202>3.0.CO;2-L CAS PubMed Web of Science® Google Scholar
- 24Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Primers. 2019; 5(1): 1.
- 25Sotiriou C, Wirapati P, Loi S, et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J Natl Cancer Inst. 2006; 98(4): 262-272.
