Dataset Information

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

ABSTRACT:

Background

Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults.

Methods

To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines.

Results

Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability.

Conclusion

These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.

SUBMITTER: Rasmussen SV

PROVIDER: S-EPMC10147623 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

Rasmussen Samuel V SV Wozniak Agnieszka A Lathara Melvin M Goldenberg Joshua M JM Samudio Benjamin M BM Bickford Lissett R LR Nagamori Kiyo K Wright Hollis H Woods Andrew D AD Chauhan Shefali S Lee Che-Jui CJ Rudzinski Erin R ER Swift Michael K MK Kondo Tadashi T Fisher David E DE Imyanitov Evgeny E Machado Isidro I Llombart-Bosch Antonio A Andrulis Irene L IL Gokgoz Nalan N Wunder Jay J Mirotaki Hiroshi H Nakamura Takuro T Srinivasa Ganapati G Thway Khin K Jones Robin L RL Huang Paul H PH Berlow Noah E NE Schöffski Patrick P Keller Charles C

British journal of cancer 20230323 10

<h4>Background</h4>Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults.<h4>Methods</h4>To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first appro ...[more]

PMID: 36959380

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Project description:BackgroundThe genomic background affects the occurrence and metastasis of cancers, including clear cell renal cell carcinoma (ccRCC). However, reports focusing on the prognostic mutational signature of Chinese ccRCC are lacking.MethodsOverall, 929 patients, including a training cohort with Chinese patients (n = 201), a testing cohort with Caucasian patients (n = 274), and a validation cohort (n = 454) were analyzed for the genomic landscape of ccRCC. Then, machine-learning algorithms were used to identify and evaluate the genomic mutational signature (GMS) in ccRCC. Analyses for prognosis, immune microenvironment, association with independent clinicopathological features, and predictive responses for immune checkpoint therapies (ICTs) were performed.ResultsThe DNA variation data of 929 patients with ccRCC suggested markedly differential genomic mutational frequency of the most frequent genes, such as VHL, PBRM1, BAP1, SETD2, and KDM5C between the Chinese and Caucasian populations. PBRM1 showed significant co-occurrence with VHL and SETD2. We then successfully identified a seven-gene mutational signature (GMSMut) that included mutations in FBN1, SHPRH, CELSR1, COL6A6, DST, ABCA13, and BAP1. The GMSMut significantly predicted progressive progression (P < 0.0001, HR = 2.81) and poor prognosis (P < 0.0001, HR = 3.89) in the Chinese training cohort. Moreover, ccRCC patients with the GMSMut had poor survival rates in the testing cohort (P = 0.020) and poor outcomes were predicted for those treated with ICTs in the validation cohort (P = 0.036). Interestingly, a favorable clinical response to ICTs, elevated expression of immune checkpoints, and increased abundance of tumor-infiltrated lymphocytes, specifically CD8+ T cells, Tregs, and macrophages, were observed in the GMSMut cluster.ConclusionsThis study described the pro-tumorigenic GMSMut cluster that improved the prognostic accuracy in Chinese patients with ccRCC. Our discovery of the novel independent prognostic signature highlights the relationship between tumor phenotype and genomic mutational characteristics of ccRCC.

Dataset Information

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

Background

Methods

Results

Conclusion

Publications

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

Similar Datasets

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