Genomic landscape of liposarcoma

Kanojia, Deepika; Nagata, Yasunobu; Garg, Manoj; Lee, Der-Horng; Sato, Aiko; Yoshida, Kenichi; Sato, Yusuke; Sanada, Masashi; Mayakonda, Anand; Bartenhagen, Christoph; Klein, Hans Ulrich; Doan, Ngan; Said, Jonathan; Mohith, S.; Gunasekar, Swetha; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; Myklebost, Ola; Yang, Henry; Dugas, Martin; Meza‐Zepeda, Leonardo A.; Silberman, Allan W.; Forscher, Charles; Tyner, Jeffrey W.; Ogawa, Seishi; Koeffler, H. Phillip

doi:10.18632/oncotarget.6464

Cited by 105 publications

(127 citation statements)

References 47 publications

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“…In addition, we also see amplification of CPM , which has previously been reported and shown to be important for proliferation in DDLPS [25], and hemizygous deletion of NF1 , a tumor suppressor gene functionally implicated in different types of LPS [25]. All three metastases show regions previously reported as progression-associated CNAs, such as loss of 3q29, 9p22 and 10p15 [26]. We could not discern any clear hierarchy between the three metastases, but we found a surprisingly high level of dissimilarities with regard to point mutations, suggesting that most of these genomic changes are “noise” and not “drivers”.…”

Section: Discussionsupporting

confidence: 64%

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

et al. 2016

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Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis. Genomic aberrations of several potentially targetable genes, including amplification of KITLG and FRS2, in addition to amplification of CDK4 and MDM2, characteristic of this disease, were identified. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient. Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2.

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Section: Discussionsupporting

confidence: 64%

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

et al. 2016

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“…Previous studies showed heterogeneous gene expression profile in RLPS, which may generate various tumor-specific antigens and contribute to the immune heterogeneity. 34,35 Despite the challenge posed by low TILs and immunogenicity as well as large intratumoral heterogeneity, immunotherapy still has its own advantages in treating such complex tumors, as it can simultaneously activate multiple T cell subgroups. Our results suggested a higher clone expansion in RLPS than in blood samples.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive immune characterization and T‐cell receptor repertoire heterogeneity of retroperitoneal liposarcoma

et al. 2019

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Retroperitoneal liposarcoma (RLPS) is one of the most common subtypes of retroperitoneal soft tissue sarcomas and lacks effective treatment. This study aimed to provide a thorough profile of immune characteristics of RLPS. This study included 56 RLPS patients. Multisite tumor tissues were collected from 16 patients. Immunohistochemistry was carried out to identify CD4+, CD8+, FoxP3+, CD20+, or programmed cell death‐1 (PD‐1)+ tumor infiltrating lymphocytes (TILs) and Programmed cell death ligand‐1 (PD‐L1) expression in tumor tissues. Ultradeep sequencing of T‐cell receptor (TCR) β‐chain gene was carried out in 42 tumor samples as well as peripheral blood samples collected from 6 patients. In RLPS, TILs were distributed in 3 patterns and T cells were more prevalent than B cells. Generally, the proportion of TILs decreased and PD‐L1 expression increased with tumor progression. Patients with higher PD‐1/PD‐L1 expression tended to have poorer prognosis, whereas patients with tertiary lymphoid structure tended to have a favorable disease‐free survival. Although T‐cell clones in tumors were quite different from those in peripheral blood, TCR sequencing showed low TCR repertoire reads as well as polyclonal status within tumors, which indicated limited T cell response in the tumors. Both TILs distribution and TCR repertoires suggested spatial immune heterogeneity in RLPS. Our research described the immune landscape of RLPS, and suggested RLPS might be a kind of tumor with low T cell infiltration as well as great immune heterogeneity. Therefore, strategies that can facilitate lymphocytic infiltration and immune reactivity need to be developed in the future to improve the efficacy of immunotherapy.

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“…Since many tumor cells merely arrest in response to Nutlin but resume proliferation once the drug is taken off, the clinical response might be transient at best. One way to get around this problem is to select tumors with a high frequency of Mdm2 amplifications, e. g. dedifferentiated liposarcomas [6, 7]. Another way to fortify the efficacy of Nutlin and related drugs would be to combine them with additional compounds.…”

Section: Introductionmentioning

confidence: 99%

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

et al. 2016

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Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists.

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Genomic landscape of liposarcoma

Cited by 105 publications

References 47 publications

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

Comprehensive immune characterization and T‐cell receptor repertoire heterogeneity of retroperitoneal liposarcoma

Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity

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