[Metastatic paratesticular liposarcoma].
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ABSTRACT:
SUBMITTER: Fahsi O
PROVIDER: S-EPMC5554628 | biostudies-other | 2017
REPOSITORIES: biostudies-other
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Project description:BackgroundMyxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.MethodsThis retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.ResultsLung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED.ConclusionsThis is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.
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Project description:Liposarcoma is one of the most common subtypes of soft-tissue sarcoma and consists of three main subtypes, of which well-differentiated liposarcoma and dedifferentiated liposarcoma account for 40-45%. The current mainstay of systemic treatment for patients with metastatic or unresectable disease remains doxorubicin with or without ifosfamide in the first-line setting. Recently, eribulin and trabectedin have been approved by the US Food and Drug Administration for recurrent liposarcomas and progress in molecular characterization of these tumors has opened up new and potential novel treatment targets. This review will focus on the evidence base for current treatment strategies and will also discuss potential future options.
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Project description:Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.
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Project description:The Architecture and Evolution of Cancer Neochromosomes
| PRJEB4696 | ENA
Project description:Liposarcomas are aggressive mesenchymal cancers with poor outcomes that exhibit remarkable histologic diversity (there are five recognized subtypes). Currently, the mainstay of therapy for liposarcoma is surgical excision because liposarcomas are often resistant to traditional chemotherapy. In light of the high mortality associated with liposarcoma and the lack of effective systemic therapy, we sought novel genomic alterations driving liposarcomagenesis that might serve as therapeutic targets. ZIC1, a critical transcription factor for neuronal development, is overexpressed in all five subtypes of liposarcoma compared with normal fat, and in liposarcoma cell lines compared with adipose-derived stem cells. Here, we show that ZIC1 contributes to the pathogenesis of liposarcoma. ZIC1 knockdown inhibits proliferation, reduces invasion, and induces apoptosis in dedifferentiated and myxoid/round cell liposarcoma cell lines, but not in either adipose-derived stem cells or in a lung cancer cell line with low ZIC1 expression. ZIC1 knockdown is associated with increased nuclear expression of p27 proteins and the downregulation of prosurvival target genes BCL2L13, JunD, Fam57A, and EIF3M. Our results show that ZIC1 expression is essential for liposarcomagenesis and that targeting ZIC1 or its downstream targets might lead to novel therapy for liposarcoma.
| S-EPMC3266950 | biostudies-literature
Project description:Liposarcomas are rare malignant tumors of adipocytic differentiation. The classification of liposarcomas into four principal subtypes reflects the distinct clinical behavior, treatment sensitivity, and underlying biology encompassed by these diseases. Increasingly, clinical management decisions and the development of investigational therapeutics are informed by an improved understanding of subtype-specific molecular pathology. Well-differentiated liposarcoma is the most common subtype and is associated with indolent behavior, local recurrence, and insensitivity to radiotherapy and chemotherapy. Dedifferentiated liposarcoma represents focal progression of well-differentiated disease into a more aggressive, metastasizing, and fatal malignancy. Both of these subtypes are characterized by recurrent amplifications within chromosome 12, resulting in the overexpression of disease-driving genes that have been the focus of therapeutic targeting. Myxoid liposarcoma is characterized by a pathognomonic chromosomal translocation that results in an oncogenic fusion protein, whereas pleomorphic liposarcoma is a karyotypically complex and especially poor-prognosis subtype that accounts for less than 10% of liposarcoma diagnoses. A range of novel pharmaceutical agents that aim to target liposarcoma-specific biology are under active investigation and offer hope of adding to the limited available treatment options for recurrent or inoperable disease.
| S-EPMC5759315 | biostudies-literature
Project description:BackgroundAtypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.ResultsThe present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q.ConclusionsThe observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.
| S-EPMC5483303 | biostudies-literature
Project description:TRIAL INFORMATION:ClinicalTrials.gov Identifier: NCT02048371 Sponsors: SARC, with support from Bayer HealthCare Pharmaceuticals (Berlin, Germany) Principal Investigator: Richard F. Riedel IRB Approved: Yes LESSONS LEARNED: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. BACKGROUND:Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. METHODS:Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3?weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. RESULTS:Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. CONCLUSION:Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.
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Project description:Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM) However, genomic changes associated with progression from WD to DD have not been well-defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor.
| S-EPMC5880260 | biostudies-literature
Project description:Well-differentiated liposarcoma (WDLPS), one of the most common human sarcomas, is poorly responsive to radiation and chemotherapy, and the lack of animal models suitable for experimental analysis has seriously impeded functional investigation of its pathobiology and development of effective targeted therapies. Here, we show that zebrafish expressing constitutively active Akt2 in mesenchymal progenitors develop WDLPS that closely resembles the human disease. Tumor incidence rates were 8% in p53 wild-type zebrafish, 6% in p53 heterozygotes, and 29% in p53-homozygous mutant zebrafish (P = 0.013), indicating that aberrant Akt activation collaborates with p53 mutation in WDLPS pathogenesis. Analysis of primary clinical specimens of WDLPS, and of the closely related dedifferentiated liposarcoma (DDLPS) subtype, revealed immunohistochemical evidence of AKT activation in 27% of cases. Western blot analysis of a panel of cell lines derived from patients with WDLPS or DDLPS revealed robust AKT phosphorylation in all cell lines examined, even when these cells were cultured in serum-free media. Moreover, BEZ235, a small molecule inhibitor of PI3K and mammalian target of rapamycin that effectively inhibits AKT activation in these cells, impaired viability at nanomolar concentrations. Our findings are unique in providing an animal model to decipher the molecular pathogenesis of WDLPS, and implicate AKT as a previously unexplored therapeutic target in this chemoresistant sarcoma.
| S-EPMC3182699 | biostudies-literature