The Nanocind Signature Is an Independent Prognosticator of Recurrence and Death in Uterine Leiomyosarcomas

Croce, Sabrina; Lesluyes, Tom; Valle, Carine; Mhamdi, Loubna; Thébault, Noémie; Pérot, Gaëlle; Stoeckle, Eberhard; Noël, Jean‐Christophe; Fontanges, Quitterie; Devouassoux‐Shisheboran, Mojgan; Querleu, Denis; Guyon, Frédéric; Floquet, Anne; Chakiba, Camille; Mayeur, Laétitia; Rebier, Flora; MacGrogan, Gaëtan; Soubeyran, Isabelle; Guellec, Sophie Le; Chibon, Fréderic

doi:10.1158/1078-0432.ccr-19-2891

Cited by 16 publications

(10 citation statements)

References 33 publications

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“…A recent study on uterine sarcomas was performed, showing that potentially actionable mutations were identified in nearly half of the analyzed patients, even if the study confirmed the recurrent mutational profile of uLMS dictated by TP53 , RB1 and ATRX genetic hits [ 19 ]. Even if novel genetic signatures are discovered and proposed to stratify patients with respect to prognosis [ 20 ], their impact on the clinical management of patients or on the development of novel therapeutic opportunities is still marginal.…”

Section: Introductionmentioning

confidence: 99%

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Astolfi

Nannini

Indio

et al. 2020

Cancers

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Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in either TP53, RB1, ATRX or PTEN. The most frequently mutated gene was TP53, with 61% of the patients harboring at least one mutation, followed by RB1 at 48%. PTEN alteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend for TP53 and RB1 mutations to occur together, while both TP53 and RB1 were mutually exclusive with respect to CDKN2A/B inactivation. Overall survival did not show significant correlation with the mutational status, even if RB1 mutation emerged as a favorable prognostic factor in the TP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis.

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Section: Introductionmentioning

confidence: 99%

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Astolfi

Nannini

Indio

et al. 2020

Cancers

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“…The signature demonstrated its prognostic value in a series of 60 ULMS by identifying a group of patients with low risk of recurrence and death with a 5‐year RFS of 51% and a 5‐year OS of 86% vs a 5‐year RFS of 9% and 5‐year OS 29% for the high‐risk group (Figure 3A,B) (RFS: P = 6.7×10 −4 , HR = 3.71) (OS: P = 7.56×10 −4 , HR = 5.97). Thus, in multivariate analysis, it outperformed the GI at the threshold of 35, which was prognostic for OS but not for RFS 60 …”

Section: Genomic Complexity and Uterine Smooth Muscle Tumorsmentioning

confidence: 92%

“…The pertinence of the CINSARC signature in ULMS was demonstrated in stage 1 ULMS with 5‐year OS of 84% and 5‐year RFS of 59% for the low‐risk group vs 39% of 5‐year OS and 15% 5‐year RFS for the high‐risk group (OS P = 9.89×10 −3 ; HR = 5.51) (RFS P = 3.38×10 −3 ; HR = 3.83). Again, in multivariate analysis, it outperformed the GI at the cutoff of 35 and atypia 60 (Figure 4A‐C). These results were validated in an independent cohort (32 ULMS) from TCGA 51 .…”

Section: Genomic Complexity and Uterine Smooth Muscle Tumorsmentioning

confidence: 95%

Molecular prognostication of uterine smooth muscle neoplasms: FromCGHarray toCINSARCsignature and beyond

Croce

Chibon

2020

Genes Chromosomes & Cancer

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Uterine leiomyoma and leiomyosarcoma are located at the ends of the spectrum of smooth muscle lesions. Leiomyosarcoma belongs to the complex genomic sarcomas characterized by complex karyotypes. In contrast, leiomyoma, has a low level of chromosomal complexity. The analysis of genomic profiles of uterine smooth muscle tumors shows that genomic complexity, which is an expression of chromosomal instability, correlates with the metastatic potential and malignity of tumors: the more genetically complex a smooth muscle tumor is, the more malignant is its progression. In uterine tumors with uncertain malignant potential, the assessment of genomic index by CGH array, that is, counting the genomic complexity of a tumor, allows tumors with a risk of recurrence such as leiomyosarcomas to be distinguished from benign tumors like leiomyomas. The prognosis of leiomyosarcoma is poor and the most powerful prognostic factor so far is stage, as the histologic grade is not informative. In the quest to find efficient molecular prognostic factors, the transcriptomic signature CINSARC Nanocind, a mirror of chromosomic complexity and instability, outperforms stage, in both overall and recurrence‐free survival. Genomic index and the CINSARC signature will contribute to improving diagnoses, therapeutic strategies, and randomization in future clinical trials. The biological understanding of the links between the CINSARC signature and metastatic mechanisms may lead to the development of new drugs. Furthermore, ctDNA is a promising new technique to detect residual disease and early recurrence.

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“…FIGO staging remains the primary prognostic factor, alongside an uLMSspecific nomogram for predicting post-resection 5-year OS 39,40 . There is a need for improved prognosticators to identify patients who might benefit from adjuvant chemotherapy 41 . Italiano et al showed that CINSARC classified 73 primary LMS, of multiple anatomical locations, into two groups with significantly different MFS 42 .…”

Section: Introductionmentioning

confidence: 99%

“…Italiano et al showed that CINSARC classified 73 primary LMS, of multiple anatomical locations, into two groups with significantly different MFS 42 . In a retrospective series of 60 uLMS CINSARC divided this cohort, of all FIGO stages, into high-risk (C2) and low-risk (C1) groups 41 . C2 had 5-year relapse-free survival (RFS) rate of 9% compared to 51% in C1.…”

Section: Introductionmentioning

confidence: 99%

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas

et al. 2021

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Soft tissue sarcomas (STS) are rare and heterogeneous tumours comprising over 80 different histological subtypes. Treatment options remain limited in advanced STS with high rates of recurrence following resection of localised disease. Prognostication in clinical practice relies predominantly on histological grading systems as well as sarcoma nomograms. Rapid developments in gene expression profiling technologies presented opportunities for applications in sarcoma. Molecular profiling of sarcomas has improved our understanding of the cancer biology of these rare cancers and identified potential novel therapeutic targets. In particular, transcriptomic signatures could play a role in risk classification in sarcoma to aid prognostication. Unlike other solid and haematological malignancies, transcriptomic signatures have not yet reached routine clinical use in sarcomas. Herein, we evaluate early developments in gene expression profiling in sarcomas that laid the foundations for transcriptomic signature development. We discuss the development and clinical evaluation of key transcriptomic biomarker signatures in sarcomas, including Complexity INdex in SARComas (CINSARC), Genomic Grade Index, and hypoxia-associated signatures. Prospective validation of these transcriptomic signatures is required, and prospective trials are in progress to evaluate reliability for clinical application. We anticipate that integration of these gene expression signatures alongside existing prognosticators and other Omics methodologies, including proteomics and DNA methylation analysis, could improve the identification of ‘high-risk’ patients who would benefit from more aggressive or selective treatment strategies. Moving forward, the incorporation of these transcriptomic prognostication signatures in clinical practice will undoubtedly advance precision medicine in the routine clinical management of sarcoma patients.

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The Nanocind Signature Is an Independent Prognosticator of Recurrence and Death in Uterine Leiomyosarcomas

Cited by 16 publications

References 33 publications

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Molecular prognostication of uterine smooth muscle neoplasms: FromCGHarray toCINSARCsignature and beyond

Predictive and prognostic transcriptomic biomarkers in soft tissue sarcomas

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