Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma

Gounder, Mrinal M.; Agaram, Narasimhan P.; Trabucco, Sally E.; Robinson, Victoria; Ferraro, Richard; Millis, Sherri Z.; Krishnan, Anita; Lee, Jessica; Attia, Steven; Abida, Wassim; Drilon, Alexander; Chi, Ping; D’Angelo, Sandra P.; Dickson, Mark A.; Keohan, Mary Lou; Kelly, Ciara M.; Agulnik, Mark; Chawla, Sant P.; Choy, Edwin; Chugh, Rashmi; Meyer, Christian F.; Myer, Parvathi A.; Moore, Jessica L.; Okimoto, Ross A.; Pollock, Raphael E.; Ravi, Vinod; Singh, Arun S.; Somaiah, Neeta; Wagner, Andrew J.; Healey, John H.; Frampton, Garrett M.; Venstrom, Jeffrey M.; Ross, Jeffrey S.; Ladanyi, Marc; Singer, Samuel; Brennan, Murray F.; Schwartz, Gary K.; Lazar, Alexander J.; Thomas, David M.; Maki, Robert G.; Tap, William D.; Ali, Siraj M.; Jin, Dexter X.

doi:10.1038/s41467-022-30496-0

Cited by 92 publications

(93 citation statements)

References 94 publications

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“…Moreover, two members of the Fanconi anemia core complex, FANCA and FANCB,t h eTP53 regulator MDM2,t h e tumor suppressor PTEN, cell cycle checkpoint regulators RAD1 and CHEK1, DNA damage and replication proteins ATM, RPA1 and H2AFX completed the list of the 10 top altered HRR genes in the TCGA-SARC cohort. Our genomic analyses are in line with recently published work (Gounder et al, 2022;N a c e vet al, 2022)t h a t described molecular patterns and genomic instability signatures in distinct sarcoma histotypes using a large cohort of sarcoma patients. In contrast to their findings, we identified a significant number of gene alterations in an extended HRR gene set, thus contributing to elucidate potential molecular mechanisms for HRDness in distinct sarcoma histotypes.…”

Section: Discussionsupporting

confidence: 88%

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRD high sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

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Section: Discussionsupporting

confidence: 88%

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Planas-Paz¹,

Pliego-Mendieta²,

Hagedorn³

et al. 2023

EMBO Mol Med

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“…In this regard, an example is the case of MFS and UPS representing two separate STS entities previously grouped under the name of malignant fibrous histiocytoma that are both characterized by the unavailability of both diagnostic and prognostic biomarkers and generally harbor highly complex karyotypes [ 11 , 12 ]. Moreover, the lack of predictive biomarkers that could guide physicians in the therapy selection represents a critical issue in the clinical management of STS, including these two entities [ 13 ]. In this work, we took advantage of an integrated approach combining the translational strength of patient-derived primary cultures as a powerful tool for the study of pathophysiology and of the pharmacological profile of STS, together with genomic profiling techniques in order to identify promising biomarkers for the stratification of MFS and UPS patients for the most suitable chemotherapeutic treatment.…”

Section: Discussionmentioning

confidence: 99%

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need

Vanni

Fausti

Fonzi

et al. 2023

IJMS

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Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) can be considered as a spectrum of the same disease entity, representing one of the most common adult soft tissue sarcoma (STS) of the extremities. While MFS is rarely metastasizing, it shows an extremely high rate of multiple frequent local recurrences (50–60% of cases). On the other hand, UPS is an aggressive sarcoma prone to distant recurrence, which is correlated to a poor prognosis. Differential diagnosis is challenging due to their heterogeneous morphology, with UPS remaining a diagnosis of exclusion for sarcomas with unknown differentiation lineage. Moreover, both lesions suffer from the unavailability of diagnostic and prognostic biomarkers. In this context, a genomic approach combined with pharmacological profiling could allow the identification of new predictive biomarkers that may be exploited for differential diagnosis, prognosis and targeted therapy, with the aim to improve the management of STS patients. RNA-Seq analysis identified the up-regulation of MMP13 and WNT7B in UPS and the up-regulation of AKR1C2, AKR1C3, BMP7, and SGCG in MFS, which were confirmed by in silico analyses. Moreover, we identified the down-regulation of immunoglobulin genes in patient-derived primary cultures that responded to anthracycline treatment compared to non-responder cultures. Globally, the obtained data corroborated the clinical observation of UPS as an histotype refractory to chemotherapy and the key role of the immune system in determining chemosensitivity of these lesions. Moreover, our results confirmed the validity of genomic approaches for the identification of predictive biomarkers in poorly characterized neoplasms as well as the robustness of our patient-derived primary culture models in recapitulating the chemosensitivity features of STS. Taken as a whole, this body of evidence may pave the way toward an improvement of the prognosis of these rare diseases through a treatment modulation driven by a biomarker-based patient stratification.

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“…From UCSC (see Footnote 5) database we had downloaded a standardized pan-cancer dataset: TCGA Pan Cancer (PANCAN, N = 10,535, G = 60,499). Based on the previously extracted expression data and screened samples, we obtained MSI (Microsatellite instance) scores of each tumor from the previous study ( Gounder et al, 2022 ). Next, the MSI and gene expression data of the samples were integrated.…”

Section: Methodsmentioning

confidence: 99%

Systematic analysis of virus nucleic acid sensor DDX58 in malignant tumor

Huang

Jin

et al. 2022

Front. Microbiol.

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IntroductionIn December 2019, a novel epidemic of coronavirus pneumonia (COVID-19) was reported，and population-based studies had shown that cancer was a risk factor for death from COVID-19 infection. However, the molecular mechanism between COVID-19 and cancer remains indistinct. In this paper, we analyzed the nucleic acid sensor (DDX58) of SARS-CoV-2 virus, which is a significant gene related to virus infection. For purpose of clarifying the characteristics of DDX58 expression in malignant tumors, this study began to systematically analyze the DDX58 expression profile in the entire cancer type spectrum.MethodsUsing TCGA pan-cancer database and related data resources, we analyzed the expression, survival analysis, methylation expression, mutation status, microsatellite instability (MSI), immune related microenvironment, gene related network, function and drug sensitivity of DDX58.ResultsThe expression level of DDX58 mRNA in most cancers was higher than the expression level in normal tissues. Through TIMER algorithm mining, we found that DDX58 expression was closely related to various levels of immune infiltration in pan-cancer. The promoter methylation level of DDX58 was significantly increased in multiple cancers. In addition, abnormal expression of DDX58 was related to MSI and TMB in multiple cancers, and the most common type of genomic mutation was “mutation.” In the protein–protein interaction (PPI) network, we found that type I interferon, phagocytosis, ubiquitinase, and tumor pathways were significantly enriched. Finally, according to the expression of DDX58 indicated potential sensitive drugs such as Cediranib, VE−821, Itraconazole, JNJ−42756493, IWR−1, and Linsitinib.DiscussionIn conclusion, we had gained new insights into how DDX58 might contribute to tumor development, and DDX58 could be used as an immune-related biomarker and as a potential immunotherapeutic target for COVID-19 infected cancer patients.

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Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma

Cited by 92 publications

References 94 publications

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Unveiling the Genomic Basis of Chemosensitivity in Sarcomas of the Extremities: An Integrated Approach for an Unmet Clinical Need

Systematic analysis of virus nucleic acid sensor DDX58 in malignant tumor

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