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Proteomic profiling improves prognostic risk stratification of the Sarculator nomogram in soft tissue sarcomas of the extremities and trunk wall

Background High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outco...

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Main Authors: Chadha, Madhumeeta (Author) , Iadecola, Sara (Author) , Jenks, Andrew (Author) , Pankova, Valeriya (Author) , Tam, Yuen Bun (Author) , Burns, Jessica (Author) , Arthur, Amani (Author) , Wilding, Christopher P. (Author) , Chen, Liang (Author) , Chudasama, Priya (Author) , Callegaro, Dario (Author) , Strauss, Dirk C. (Author) , Thway, Khin (Author) , Gronchi, Alessandro (Author) , Jones, Robin L. (Author) , Miceli, Rosalba (Author) , Pasquali, Sandro (Author) , Huang, Paul H. (Author)
Format: Article (Journal)
Language:English
Published: 23 July 2024
In: Cancer medicine
Year: 2024, Volume: 13, Issue: 14, Pages: 1-12
ISSN:2045-7634
DOI:10.1002/cam4.70026
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/cam4.70026
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/cam4.70026
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Author Notes:Madhumeeta Chadha, Sara Iadecola, Andrew Jenks, Valeriya Pankova, Yuen Bun Tam, Jessica Burns, Amani Arthur, Christopher P. Wilding, Liang Chen, Priya Chudasama, Dario Callegaro, Dirk C. Strauss, Khin Thway, Alessandro Gronchi, Robin L. Jones, Rosalba Miceli, Sandro Pasquali, Paul H. Huang
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Summary:Background High-risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline-based therapy compared to low/intermediate-risk patients. The biology underpinning these differential treatment outcomes remain unknown. Methods We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature-Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. Results DNA replication and cell cycle proteins were upregulated in high-risk versus very low-risk patients. Evaluation of the functional effects of CRISPR-Cas9 gene knockdown of proteins enriched in high-risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e-06), histology (p = 1.4e-05) and risk groups (p = 2.6e-06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). Conclusions Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next-generation nomograms.
Item Description:Gesehen am 24.02.2024
Physical Description:Online Resource
ISSN:2045-7634
DOI:10.1002/cam4.70026

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