CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond

Chibon, Fréderic; Lesluyes, Tom; Valentin, Thibaud; Guellec, Sophie Le

doi:10.1002/gcc.22703

Cited by 30 publications

(20 citation statements)

References 49 publications

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“…We also constructed two comprehensive nomograms with satisfactory AUCs (OS: 0.832–0.926, PFS: 0.776–0.874) based on independent variables to assess the deterioration and survival of patients. To date, numerous studies have developed signatures based on sequencing data to stratify sarcoma patients, including CINSARC [ 64 ], alternative splicing events [ 65 ], relapse-related genes [ 66 ], and lncRNA [ 67 ]. However, none of them has been applied in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Chen

Huang

et al. 2020

J Transl Med

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Background: Immune-related genes (IRGs) have been confirmed to have an important role in tumorigenesis and tumor microenvironment formation. Nevertheless, a systematic analysis of IRGs and their clinical significance in soft tissue sarcoma (STS) patients is lacking. Methods: Gene expression files from The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) were used to select differentially expressed genes (DEGs). Differentially expressed immune-related genes (DEIRGs) were determined by matching the DEG and ImmPort gene sets, which were evaluated by functional enrichment analysis. Unsupervised clustering of the identified DEIRGs was conducted, and associations with prognosis, the tumor microenvironment (TME), immune checkpoints, and immune cells were analyzed simultaneously. Two prognostic signatures, one for overall survival (OS) and one for progression free survival (PFS), were established and validated in an independent set. Finally, two transcription factor (TF)-IRG regulatory networks were constructed, and a crucial regulatory axis was validated. Results: In total, 364 DEIRGs and four clusters were identified. OS, TME scores, five immune checkpoints, and 12 types of immune cells were found to be significantly different among the four clusters. The two prognostic signatures incorporating 20 DEIRGs showed favorable discrimination and were successfully validated. Two nomograms combining signature and clinical variables were generated. The C-indexes were 0.879 (95%CI 0.832 ~ 0.926) and 0.825 (95%CI 0.776 ~ 0.874) for the OS and PFS signatures, respectively. Finally, TF-IRG regulatory networks were established, and the MYH11-ADM regulatory axis was verified in three independent datasets. Conclusion: This comprehensive analysis of the IRG landscape in soft tissue sarcoma revealed novel IRGs related to carcinogenesis and the immune microenvironment. These findings have implications for prognosis and therapeutic responses, which reveal novel potential prognostic biomarkers, promote precision medicine, and provide potential novel targets for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Chen

Huang

et al. 2020

J Transl Med

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“…Overall there is a strong rationale warranting a target selection design to validate the role of the CINSARC signature in G1/2 STS sarcoma [10,13]. In the best-case scenario, this trial will confirm the value of perioperative chemotherapy in G1/2 STS presenting HR-CINSARC in grade ½ STS treated by standard of care.…”

Section: Discussionmentioning

confidence: 84%

“…Nanostring is a recent technology with two major advantages: only needs small quantities of tumoral DNA (feasible in microbiopsies), and perfect reproducibility between different machines and centers. Optimization of CINSARC in FFPE samples using NanoString (named NanoCind®, patent number EP18305190.3) is the final step for considering the use of CINSARC on diagnostic FFPE microbiopsies in routine settings for patients with localized STS, and it can now be used to guide treatment [13].…”

Section: Cinsarc Signaturementioning

confidence: 99%

Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial

et al. 2020

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Background: The value of chemotherapy in soft tissue sarcoma (STS) remains controversial. Several expert teams consider that chemotherapy provides a survival advantage and should be proposed in high-risk (HR) patients. However, the lack of accuracy in identifying HR patients with conventional risk factors (large, deep, FNCLCC grade 3, extremity STS) is an issue that cannot be neglected. For example, while the FNCLCC grading system is a powerful tool, it has several limitations. CINSARC, a 67-gene signature, has proved to be an additional independent factor for predicting metastatic spread and outperforms histological grade. Regardless of FNCLCC grade, CINSARC stratifies patients into two separate prognostic groups: one with an excellent prognosis (low-risk (LR) CINSARC) and the other with a worse outcome (HR-CINSARC) in terms of metastatic relapse. Here we evaluate the role of chemotherapy in grade 1-2 STS patients with HR-CINSARC and assess the prognostic value of CINSARC in patients treated with standard of care. Methods: CHIC is a parallel, randomized, open-label, multicenter study evaluating the effect on metastasis-free survival of adding perioperative chemotherapy to standard of care in patients with grade ½ STS sarcoma defined as HR by CINSARC. In this target selection design, 600 patients will be screened with CINSARC to randomize 250 HR-CINSARC patients between standard of care and standard of care plus chemotherapy (4 cycles of 3 weeks of intravenous chemotherapy with doxorubicin in combination with dacarbazine or ifosfamide according to histologic subtype). LR-CINSARC patients will be treated by standard of care according to the investigator. The primary endpoint is metastasis-free survival. Secondary endpoints include overall survival, disease-free survival and safety. Furthermore, the prognostic value of CINSARC will be evaluated by comparing LR-CINSARC patients to HR-CINSARC patients randomized in standard of care.

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“…The transcriptomic Complexity Index in SARComa (CINSARC) signature is derived from the expression of 67 genes involved in chromosome biogenesis, mitosis control, and chromosome segregation (Figure 2). It is obtained by combining genes significantly differentially expressed in FNLCC grade 3 vs grade 1 and 2 sarcomas, and in tumors with a high or low level of gene rearrangement and complexity 44,57 . It was initially validated on pleomorphic sarcomas and demonstrated its prognostic value in 21 out of 39 cancers by outperforming 15 000 other signatures 58 .…”

Section: Genomic Complexity and Uterine Smooth Muscle Tumorsmentioning

confidence: 99%

“…It is now available on formalin‐fixed and paraffin‐embedded samples (FFPE) with high accuracy by Nanostring, a hybridization‐based technique adapted to FFPE material even in small quantities, such as, core biopsies 59 . The CINSARC signature adapted to FFPE, known as CINSARC Nanocind, is composed of a panel of 75 genes including the original 67 gene test probes coupled with 8 housekeeping genes for normalization purposes 57,59 …”

Section: Genomic Complexity and Uterine Smooth Muscle Tumorsmentioning

confidence: 99%

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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CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond

Cited by 30 publications

References 49 publications

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Comprehensive profiling of immune-related genes in soft tissue sarcoma patients

Value of peri-operative chemotherapy in patients with CINSARC high-risk localized grade 1 or 2 soft tissue sarcoma: study protocol of the target selection phase III CHIC-STS trial

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

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