Genetic variants and copy number changes in soft tissue leiomyosarcoma detected by targeted amplicon sequencing

2019 ◽  
Vol 72 (12) ◽  
pp. 810-816 ◽  
Author(s):  
Uma Rao ◽  
Karen Elizabeth Schoedel ◽  
Patricia Petrosko ◽  
Nozomi Sakai ◽  
William LaFramboise
Keyword(s):  
Soft Tissue ◽  
Normal Tissue ◽  
Immunohistochemical Analysis ◽  
Amplicon Sequencing ◽  
Genomic Changes ◽  
Genomic Landscape ◽  
Tissue Contamination ◽  
Copy Number Changes ◽  
Coding Variants ◽  
Matching Normal Tissue

AimsLeiomyosarcomas (LMSs) occur in various tissues and harbour potential for metastases. The genomic landscape of LMS is poorly understood. In an effort to improve understanding of the LMS genome, we analysed 11 LMSs of somatic soft tissue including matching tissue of normal phenotype.MethodsDNA derived from microdissected tumour domains and matching normal tissue underwent amplicon sequencing of 409 tumour suppressors and oncogenes using the Ion Torrent Comprehensive Cancer Panel.ResultsGenomic changes were heterogeneous with few recurrent abnormalities detected. Coding variants were identified in genes involved in signal transduction, transcriptional regulation and DNA repair. There were variants in several genes related to angiogenesis and GPR124 variants (TEM5) were confirmed by immunohistochemical analysis of a LMS tissue microarray. Surprisingly, there were shared coding variants in tumour and corresponding normal tissue.ConclusionsLMSs are a very heterogeneous population lacking recurrent somatic abnormalities. The presence of damaging mutations in normal tissue may reflect either a germline predisposition or field effect rather than tissue contamination. Hopeful therapeutic targets appear to be those related to AKT/MTOR pathway.

scholarly journals Model-Integrated Estimation of Normal Tissue Contamination for Cancer SNP Allelic Copy Number Data

2011 ◽  
Vol 10 ◽  
pp. CIN.S6873 ◽  
Author(s):  
Susann Stjernqvist ◽  
Tobias Rydén ◽  
Chris D. Greenman
Keyword(s):  
Copy Number ◽  
Normal Tissue ◽  
Index Structure ◽  
Copy Number Data ◽  
Cancer Data ◽  
Unequally Spaced ◽  
Intensity Measurements ◽  
Tissue Contamination ◽  
Continuous Index ◽  
Allelic Copy Number

SNP allelic copy number data provides intensity measurements for the two different alleles separately. We present a method that estimates the number of copies of each allele at each SNP position, using a continuous-index hidden Markov model. The method is especially suited for cancer data, since it includes the fraction of normal tissue contamination, often present when studying data from cancer tumors, into the model. The continuous-index structure takes into account the distances between the SNPs, and is thereby appropriate also when SNPs are unequally spaced. In a simulation study we show that the method performs favorably compared to previous methods even with as much as 70% normal contamination. We also provide results from applications to clinical data produced using the Affymetrix genome-wide SNP 6.0 platform.

Epithelioid Leiomyosarcoma of the External Deep Soft Tissue

2002 ◽  
Vol 126 (4) ◽  
pp. 468-470 ◽  
Author(s):  
Tetsuji Yamamoto ◽  
Rieko Minami ◽  
Chiho Ohbayashi ◽  
Mayumi Inaba
Keyword(s):  
Soft Tissue ◽  
Tumor Cells ◽  
Epithelial Membrane Antigen ◽  
Spindle Cell ◽  
Smooth Muscle Actin ◽  
S100 Protein ◽  
Immunohistochemical Analysis ◽  
Deep Soft Tissue ◽  
Cell Component ◽  
Spindle Cell Component

Abstract Epithelioid leiomyosarcoma in the external deep soft tissue is extremely rare. Most epithelioid leiomyosarcomas occur in the uterus. We present a case of epithelioid leiomyosarcoma occurring in the muscle of the thigh of a 78-year-old man. Histologically, the tumor predominantly consisted of round or polygonal cells arranged in sheets with a focal spindle cell component. Immunohistochemical analysis revealed that the tumor cells expressed vimentin, α-smooth muscle actin, and α-sarcomeric actin. The tumor was negative for desmin, S100 protein, glial fibrillary acidic protein, pan-keratin, epithelial membrane antigen, CAM 5.2, HMB-45, leukocyte common antigen, factor VIII–associated antigen, and CD34. Electron microscopically, some tumor cells contained abundant actin-type filaments in their cytoplasm.

scholarly journals Neoadjuvant Radiotherapy-Related Wound Morbidity in Soft Tissue Sarcoma: Perspectives for Radioprotective Agents

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2258
Author(s):  
Cameron M. Callaghan ◽  
M. M. Hasibuzzaman ◽  
Samuel N. Rodman ◽  
Jessica E. Goetz ◽  
Kranti A. Mapuskar ◽  
...  
Keyword(s):  
Wound Healing ◽  
Soft Tissue ◽  
Adjuvant Radiotherapy ◽  
Normal Tissue ◽  
Soft Tissue Sarcomas ◽  
Limb Amputation ◽  
Neoadjuvant Radiotherapy ◽  
Normal Tissue Toxicity ◽  
Radiation Induced ◽  
Intensity Radiation

Historically, patients with localized soft tissue sarcomas (STS) of the extremities would undergo limb amputation. It was subsequently determined that the addition of radiation therapy (RT) delivered prior to (neoadjuvant) or after (adjuvant) a limb-sparing surgical resection yielded equivalent survival outcomes to amputation in appropriate patients. Generally, neoadjuvant radiation offers decreased volume and dose of high-intensity radiation to normal tissue and increased chance of achieving negative surgical margins—but also increases wound healing complications when compared to adjuvant radiotherapy. This review elaborates on the current neoadjuvant/adjuvant RT approaches, wound healing complications in STS, and the potential application of novel radioprotective agents to minimize radiation-induced normal tissue toxicity.

scholarly journals Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma

2016 ◽  
Vol 34 (26) ◽  
pp. 3166-3174 ◽  
Author(s):  
Mrinal M. Gounder ◽  
Alona Zer ◽  
William D. Tap ◽  
Samer Salah ◽  
Mark A. Dickson ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Nuclear Export ◽  
Drug Exposure ◽  
Objective Response ◽  
Immunohistochemical Analysis ◽  
Bone Sarcoma ◽  
Preliminary Evidence ◽  
Nuclear Accumulation ◽  
Flat Dose ◽  
Tumor Biopsies

Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. Results The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Conclusion Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

scholarly journals A genomic epidemiology investigation of yaws re-emergence and bacterial drug resistance selection

2020 ◽  
Author(s):  
Mathew A Beale ◽  
Marc Noguera-Julian ◽  
Charmie Godornes ◽  
Maria Casadella ◽  
Camila Gonzalez-Beiras ◽  
...  
Keyword(s):  
Drug Resistance ◽  
General Population ◽  
Spatial Information ◽  
Bacterial Genome ◽  
Treponema Pallidum ◽  
Index Patient ◽  
Amplicon Sequencing ◽  
Sequence Type ◽  
Genomic Changes ◽  
Bacterial Drug Resistance

Background: In a longitudinal study assessing the WHO strategy for yaws eradication using mass azithromycin treatment, we observed resurgence of yaws cases with dominance of a single JG8 sequence type and emergence of azithromycin-resistant Treponema pallidum. Here, we analyse genomic changes in the bacterial population using samples collected during the study. Methods: We performed whole bacterial genome sequencing directly on DNA extracted from 37 lesion swabs collected from patients on Lihir Island, Papua New Guinea, between 2013 and 2016. We produced phylogenies and correlated these with temporo-spatial information to investigate the source of new cases and the emergence of five macrolide-resistant cases. We used deep amplicon sequencing of surveillance samples to assess the presence of minority macrolide resistance populations. Findings: We recovered 20 whole Treponema genomes, and phylogenetic analysis showed that the re-emerging JG8 sequence type was composed of three bacterial sub-lineages characterised by distinct temporo-spatial patterns. Of five patients with resistant Treponema, all epidemiologically linked, we recovered genomes from three and found no variants. Deep sequencing showed that pre-treatment, the index patient harboured fixed macrolide-sensitive Treponema, while the post-treatment sample harboured a fixed resistant genotype, as did three of four contact cases. We also found no evidence of pre-existing minority Treponema drug-resistance variants in the general population. Interpretation: In this study, re-emergence of yaws cases was polyphyletic, indicating multiple epidemiological sources. However, given the genomic and epidemiological linkage of resistant cases and the rarity of resistance alleles in the general population, it is likely that azithromycin resistance evolved only once in this study, followed by onward dissemination.

scholarly journals Genomic landscape of gliosarcoma: distinguishing features and targetable alterations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark M. Zaki ◽  
Leila A. Mashouf ◽  
Eleanor Woodward ◽  
Pinky Langat ◽  
Saksham Gupta ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Information Exchange ◽  
Predictive Biomarker ◽  
Disease Classification ◽  
Sequencing Data ◽  
Genomic Signatures ◽  
Molecular Features ◽  
Genomic Landscape ◽  
Distinguishing Features

AbstractGliosarcoma is an aggressive brain tumor with histologic features of glioblastoma (GBM) and soft tissue sarcoma. Despite its poor prognosis, its rarity has precluded analysis of its underlying biology. We used a multi-center database to characterize the genomic landscape of gliosarcoma. Sequencing data was obtained from 35 gliosarcoma patients from Genomics Evidence Neoplasia Information Exchange (GENIE) 5.0, a database curated by the American Association of Cancer Research (AACR). We analyzed genomic alterations in gliosarcomas and compared them to GBM (n = 1,449) and soft tissue sarcoma (n = 1,042). 30 samples were included (37% female, median age 59 [IQR: 49–64]). Nineteen common genes were identified in gliosarcoma, defined as those altered in > 5% of samples, including TERT Promoter (92%), PTEN (66%), and TP53 (60%). Of the 19 common genes in gliosarcoma, 6 were also common in both GBM and soft tissue sarcoma, 4 in GBM alone, 0 in soft tissue sarcoma alone, and 9 were more distinct to gliosarcoma. Of these, BRAF harbored an OncoKB level 1 designation, indicating its status as a predictive biomarker of response to an FDA-approved drug in certain cancers. EGFR, CDKN2A, NF1, and PTEN harbored level 4 designations in solid tumors, indicating biological evidence of these biomarkers predicting a drug-response. Gliosarcoma contains molecular features that overlap GBM and soft tissue sarcoma, as well as its own distinct genomic signatures. This may play a role in disease classification and inclusion criteria for clinical trials. Gliosarcoma mutations with potential therapeutic indications include BRAF, EGFR, CDKN2A, NF1, and PTEN.

Comprehensive Ultra High Resolution Analysis of Copy Number and Allele Status Including Novel Microdeletions Spanning NF1 in Acute Myelogenous Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3107-3107
Author(s):  
Sami Malek ◽  
Peter Ouillette ◽  
Whitney Wright ◽  
Amanda Dressel ◽  
Judy Karp ◽  
...  
Keyword(s):  
Copy Number ◽  
Mutational Analysis ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Ras Pathway ◽  
Genomic Changes ◽  
Large Deletions ◽  
Allele Status ◽  
High Resolution Analysis ◽  
Copy Number Changes

Abstract Karyotypic abnormalities are of dominant importance in AML risk prognostication and therapy selection. A comprehensive description of subchromosomal genomic copy number changes and allele status together with gene mutation analysis and identification of chromosomal translocations is needed to fully harvest the prognostic and biological power of genomic changes in AML. We have analyzed DNA from 96 AML-derived pure blast populations (purified using column-based multi parameter negative selection followed by multi-gated FACS sorting) compared with paired buccal DNA using the Affymetrix 6.0 SNP platform. To support data analysis and display, we have developed the software tools PLUT and LOH tool version 2 and have refined dChipSNP. Data were supplemented with blast karyotypes and mutation status of Flt3, NPM1, p53, N-ras and K-ras. Results: AML cases carried between zero and thirty-four subchromosomal losses and gains. Approximately 23% of all cases had ≥3 subchromosomal lesions and approximately 50% of all cases had no such lesions. Of the 22 cases with complex and hypercomplex genomic changes by SNP profiling, ~50% had mutations in p53 exons 5–9 and ~50% were p53 wild-type by sequence analysis. Monoallelic deletion of p53 as part of various deletions at 17p was found in 7 of 96 (7%) cases. Importantly, 7/96=7% additional cases demonstrated UPD at 17p which spanned the p53 locus. Of all 14/96=15% of cases with LOH at 17p (with and without copy loss) 9/14=64% carried p53 mutations and 11/14=79% had complex karyotypes. Of the AML cases with NPM1 mutations (19 of 96 cases or 20%), 75% carried no detectable subchromosomal lesions, while 25% carried between 1 and 4 such lesions. Previously unidentified microdeletions resulting in monoallelic NF1 loss were identified on 17p in a total of 10 of 96 (10%) cases, thus suggesting activation of the Ras pathway independent of Ras mutations (all affected cases had wild-type N-ras and K-ras) in a substantial subset of AML cases. Mutational analysis of all coding exons of NF1 on the retained allele in the affected cases is ongoing. Additional recurrent microdeletions were identified on chromosomes 3p and 3q as well as 12p, the latter encompassing the genes ETV6 and p27, as previously reported. Finally, analysis of the prognostically and therapeutically important deletions 5q and 7q identified large deletions without recurrent microdeletions. Regions of minimal loss on 5q have been delineated.

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