Molecular landscape and therapeutic alterations in Asian soft‐tissue sarcoma patients

Gan, Meifu; Zhang, Chen; Qiu, Liqing; Wang, Yue; Bao, Hua; Yu, Rong; Li, Rui; Wu, Xue; Shao, Yang; Hou, Peifeng; Fei, Zhenglei

doi:10.1002/cam4.4725

Cited by 5 publications

(2 citation statements)

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“…The median chromosome instability score (CIS) of this KDD cohort was 0.32, and the median tumor mutational burden (TMB) was 4.71 muts/Mb. Compared with other genomic characterization studies using similarly targeted panels, 12–15 the KDD population had a relatively low TMB, but relatively high CIS. Seven patients had a TMB value higher than 10 muts/Mb, in whom immunotherapy may be considered.…”

Section: Resultsmentioning

confidence: 73%

Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population

Lai

Yu²,

Ou³

et al. 2022

Cancer Medicine

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Background: Kinase domain duplications (KDDs) have recently been recognized as oncogenic mutations and possible association with drug resistance in cancers.Method: Here, targeted sequencing was performed with the tumor tissue and/or plasma from 65 cancer patients with KDDs.Result: Intact KDDs were identified in approximately 0.1% of the total population across multiple cancer types. EGFR KDD was first identified in colorectal cancer and breast cancer, whereas FGFR2 KDD was first identified in gastric cancer. Tumors with EGFR KDD displayed lower concurrent TP53 gene alterations (p = 0.03) and slightly higher chromosome instability (p = 0.27) compared to tumors with non-EGFR-KDDs. Immune pathway analysis further revealed the enrichment of the cytokine receptors pathway (93%) in the KDD carriers.Hyperprogression-related gene mutations were identified in four cases. Conclusion:Collectively, our data revealed the genomic features of KDD alterations in a multi-cancer cohort, providing more information for the potential treatment application in the KDD carriers.

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Section: Resultsmentioning

confidence: 73%

Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population

Lai

Yu²,

Ou³

et al. 2022

Cancer Medicine

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“…Furthermore, the predicted MSI-H rate among our RIS is 8.70%, which is higher than that of our SARC group (4.17%) and higher than that reported for primary sarcomas (2.8%; ref. 61 ). Also, we discovered a unique COSMIC signature 3 related to DNA DSB repair by HR in RIS.…”

Section: Discussionmentioning

confidence: 99%

Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade

Hong

Yang

Sun

et al. 2023

Clinical Cancer Research

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Purpose: Radiation-induced sarcomas (RISs) have poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration. Experimental Design: Here, we perform whole exome (WES) and mRNA sequencing (mRNA-seq) on patient with RISs and primary sarcomas (WES samples 46 vs 48, mRNA-seq samples 16 vs 8, mainly in head and neck), investigate the anti-tumor effect of PD-1 blockade in RIS-PDX models, and analyze clinical data of RIS patients treated with chemotherapy alone or combined with an anti-PD-1 antibody. Results: Compared to primary sarcomas, RISs manifested different pattern of copy number variations, significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher overall response rate (ORR) (36.67% vs 8.00%, p = 0.003), longer overall survival (31.9 months vs 14.8 months, p = 0.014) and longer progression free survival (4.7 months vs 9.5 months, p = 0.032) in RIS patients compared to single chemotherapy. Conclusion: Elevated genomic instability and higher immune cell infiltrations was found in RISs than primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiment and clinical practice. These evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RISs.

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Molecular landscape and therapeutic alterations in Asian soft‐tissue sarcoma patients

et al. 2022

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Background: Soft-tissue sarcoma (STS) is a rare solid malignant tumor with numerous histologic subtypes. Current studies on targeted therapy for STS are in preclinical and early-phase trials. Genomic differences largely influence the prognosis of patients even with the same subtype. To investigate the genomic alterations (GAs) and the potential of targeted therapy in STS, we analyzed the genomic landscape, the therapeutic GAs, and biomarkers of immunotherapy in Chinese STS patients.Methods: Targeted sequencing covering 425 genes was performed, from which we obtained the results of tissue samples from 351 Chinese STS patients of all ages covering different histologic subtypes. Bioinformatics analysis of altered genes with nonsynonymous mutations, copy-number variations, and gene fusions were performed. OncoKB therapeutic GAs and relevant biomarkers including TMB, MSI, and HRD were further examined for potential targeted therapy. Results:In total, 2743 GAs were identified in 330 genes with a median of 6 (1-38) per case. The top 11 frequently altered genes were: TP53, MCL1, MDM2, CDK4, MYC, CDKN2A, GNAS, RB1, ATRX, CDKN2B, and FGFR1. OncoKB defined therapeutic GAs were found in 23 genes in 43% of the patients. In general, 9.4% of the patients had high-TMB, 2.8% had MSI, and 13.7% had HRD. A significant difference in the percentage of patients with OncoKB therapeutic GAs were observed between the most frequent two subtypes, leiomyosarcoma and liposarcoma.Altogether, 54% of the patients had the potential to respond to a targeted therapy. Conclusion:This study indicated the potential efficacy of targeted therapy on many STS patients, and also provided insight for novel precision therapy. The clinical efficacy of combining targeted therapy and immunotherapy can be further investigated.

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Molecular landscape and therapeutic alterations in Asian soft‐tissue sarcoma patients

Cited by 5 publications

References 36 publications

Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population

Clinical and molecular characteristics of kinase domain duplications across diverse cancer types in the Chinese population

Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade

Molecular landscape and therapeutic alterations in Asian soft‐tissue sarcoma patients

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