scholarly journals Extensive Intratumor Proteogenomic Heterogeneity Revealed by Multiregion Sampling in High-Grade Serous Ovarian Tumor Specimens

2019 ◽  
Author(s):  
Allison L. Hunt ◽  
Nicholas W. Bateman ◽  
Waleed Barakat ◽  
Sasha Makohon-Moore ◽  
Brian L. Hood ◽  
...  
Keyword(s):  
Tumor Tissue ◽  
Molecular Subtype ◽  
Protein Microarray ◽  
Transcript Abundance ◽  
Transcript Expression ◽  
High Grade ◽  
Strongly Correlated ◽  
Thin Sections ◽  
Reverse Phase Protein Microarray ◽  
Stromal Proteins

AbstractEnriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten primary high-grade serous ovarian tumors and analyzed using proteomics (mass spectrometry and reverse phase protein microarray) and RNA-sequencing analyses. Comparative analyses of transcript and protein abundances revealed independent clustering of enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering between purified collections, driven by overall tumor purity. Comparison of historic prognostic molecular subtypes for HGSOC revealed protein and transcript expression from tumor epithelium correlated most strongly with the differentiated molecular subtype, whereas stromal proteins and transcripts most strongly correlated with mesenchymal subtype. Protein and transcript abundance in tumor epithelium and stromal collections from neighboring sections exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial protein and transcript expression heterogeneity within the tumor microenvironment that directly bears on prognostic signatures and underscore the need to enrich cellular subpopulations for expression profiling.

scholarly journals Dichotomy in Growth and Invasion From Low to High Grade Glioma Cellular Variants 

2021 ◽  
Author(s):  
Krishnendu Ghosh ◽  
Samarandranath Ghosh ◽  
Uttara Chatterjee ◽  
Pritha Bhattacharjee ◽  
Anirban Ghosh
Keyword(s):  
Tumor Tissue ◽  
High Grade Glioma ◽  
High Grade ◽  
General Increase ◽  
Grade Transition ◽  
Median Survival Period ◽  
Neoplastic Lesion ◽  
Tightly Coupled ◽  
Glial Dysfunction ◽  
Environmental Milieu

Abstract Glial dysfunction outraging CNS plasticity and integrity results into one of the most dangerous cancer, namely glioma, featuring little median survival period and high recurrence. The hallmark properties of proliferation, invasion and angiogenesis with the infiltrated macrophages in glioma are expected to be tightly coupled or cross-linked, but not definitely related so far. Present study is aimed to find a relationship between this featured quadrangle from lower to higher grades of post-operative glioma tissues and their invading subsets. Elevated Ki67 associated proliferation in lower grades was supported with VEGF dependent angiogenic maintenance which found decrease unlikely in higher grades. In contrast, MMP-2 and 9 associated invasions augmented high in higher grades with dominant presence of CD204+ M2 polarized macrophages and a general increase in global DNMT1 associated methylation. Marked differences found in ECM invading cellular subsets of higher grades showing high proliferative capacity indicating rationally for recurrence, contrasting the nature of gross tumor tissue of same grade. Thus in lower grades the neoplastic lesion is more inclined for its growth while in higher grade more disposed towards tissue wreckage in support with cellular environmental milieu whereas the cellular variants and subsets of invaded cells showed different trends. Therefore, some operational dichotomy or coupling among cellular variants in glioma is active in determining its low to high grade transition and aggressive progression.

scholarly journals Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy

2018 ◽  
Vol 78 (14) ◽  
pp. 3954-3968 ◽  
Author(s):  
Ryoichi Saito ◽  
Christof C. Smith ◽  
Takanobu Utsumi ◽  
Lisa M. Bixby ◽  
Jordan Kardos ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Molecular Subtype ◽  
High Grade

Forward-Phase and Reverse-Phase Protein Microarray

Microarrays ◽  
2007 ◽  
pp. 363-374
Author(s):  
Yaping Zong ◽  
Shanshan Zhang ◽  
Huang-Tsu Chen ◽  
Yunfei Zong ◽  
Yaxian Shi
Keyword(s):  
Protein Microarray ◽  
Reverse Phase ◽  
Phase Protein ◽  
Reverse Phase Protein Microarray

Forward-Phase and Reverse-Phase Protein Microarray

Microarrays ◽  
2007 ◽  
pp. 363-373 ◽  
Author(s):  
Yaping Zong ◽  
Shanshan Zhang ◽  
Huang-Tsu Chen ◽  
Yunfei Zong ◽  
Yaxian Shi
Keyword(s):  
Protein Microarray ◽  
Reverse Phase ◽  
Phase Protein ◽  
Reverse Phase Protein Microarray

Imatinib mesylate in the treatment of patients with recurrent high grade gliomas expressing PDGF-R

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1526-1526 ◽  
Author(s):  
C. Marosi ◽  
M. Vedadinejad ◽  
C. Haberler ◽  
J. A. Hainfellner ◽  
K. Dieckmann ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Tumor Tissue ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
High Grade ◽  
Best Response ◽  
Major Response ◽  
High Grade Gliomas ◽  
Patients Experience

1526 Background: Despite noticeable progress in the treatment of high-grade gliomas (HGG), most patients experience tumor recurrence after standard treatment consisting of surgery, radiotherapy and concomitant chemotherapy. Imatinib mesylate, a tyrosine kinase inhibitor of PDGFR-α, -β, c-kit, abl and arg, has been shown to produce tumor response in patients with recurrent gliomas (Raymond ProcASCO 2004, Dresemann ProcASCO 2004&2005, Reardon Proc ASCO 2005). We treated 34 patients with recurrent HGGs showing immunohistochemical expression of “imatinib targets” in the tumor tissue with imatinib. Methods: 34 patients, 16 women, 18 men, aged from 27 to 72 years, in median 49 years with recurrent HGG (GBM n= 23, AA n=11) were treated with imatinib 400 mg/day as continuous daily oral dosing. MRI was performed every three months or at clinical suspicion of progression. The median interval from diagnosis to the start of imatinib was 12.6 months (range 4.3 to 143 months). Imatinib was the 2nd line therapy in 15 patients, 3rd line in 13 and 4th line in 6 patients. ECOG performance score at start of imatinib was 1 in 9, 2 in 21 and 3 in 4 patients, respectively.Immunohistochemical analysis was performed on formalin fixed and paraffin embedded tumor tissue with antibodies against PDGFR-α, and -β. Results: The median treatment period with imatinib was 4 months (3 weeks to 17 months). The best response achieved was major response in 2 patients, partial remission in 6, stable disease in 12 and progressive disease in 14 patients. Eleven patients were free from tumor progression after 6 months (PFS-6 32,4%). The two patients with major response improved clinically and showed no more evidence of increased metabolism as well in MRI spectroscopy as in C11-methionine PET for 13 and 17 months, respectively. One of them showed widespread PDGF-R-α expression in the tumor tissue. In all patients with objective response to imatinib, a clinical benefit was noted within the first month of treatment. Conclusions: Compared to the results of Raymond et al, we observed a higher percentage of patients with progression free survival at 6 months. Detailed analysis of imatinib targets in tumor tissue of patients treated with imatinib will be helpful to explore the potential of imatinib as treatment option for patients with HGG. No significant financial relationships to disclose.

Circulating tumor DNA analysis using targeted sequencing of 508 clinically actionable genes in patients with high grade serous ovarian cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 5582-5582
Author(s):  
Anniina Färkkilä ◽  
Liina Salminen ◽  
Kaisa Huhtinen ◽  
Sakari Hietanen ◽  
Seija Elisa Grenman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Tissue ◽  
Genetic Alterations ◽  
Gene Panel ◽  
Targeted Sequencing ◽  
Primary Therapy ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Cancer Genes ◽  
Treatment Toxicity

5582 Background: The prediction of tumor chemoresponse and treatment toxicity is crucial for optimal patient care in high grade serous ovarian cancer (HGSC). We employed a targeted sequencing panel of 508 clinically annotated cancer genes to screen for actionable genetic variants in tumor tissue and ctDNA of patients with advanced HGSC. Methods: Tumor tissue, and serial plasma samples at diagnosis and during primary therapy were obtained from five patients with FIGO Stage IIIc HGSC. All patients were surgically debulked and received standard carboplatin and paclitaxel chemotherapy. DNA isolated from tumor tissue and plasma was analyzed for genetic alterations by targeted deep-sequencing of 508 previously annotated cancer genes. Somatic variants were systematically reported for alterations related to drug sensitivity and treatment toxicity, and analyzed with respect to clinical parameters and primary therapy outcomes. Results: In tumor tissues, and the corresponding pre-treatment ctDNA, oncogenic mutations were detected at a median of 13.0 and 1.6 allelic frequencies, respectively. The mutation frequency was higher, and also more unique mutations were detected in ctDNA of patients presenting with high tumor spread. Interestingly, a de-novo ctDNA MAPK1 mutation was detected in a sample taken during chemotherapy with partial response, while, no new mutations emerged in a patient with complete response. Analysis of the pretreatment plasma ctDNA revealed profiles of low and high drug sensitivities consistent with the clinical course of the patients. In two patients, increased risk profiles for treatment toxicities were identified via e.g. GSTP1. Consistently, these two patients were forced to discontinue standard therapy. Conclusions: Panel-based targeted sequencing of ctDNA identified potentially actionable mutations, and reflected tumor heterogeneity of HGSC. Further, the ctDNA gene panel annotations showed concordance with the chemoresponse- and treatment toxicity profiles, suggesting that ctDNA gene panel maybe a feasible approach to individualize treatment of HGSC patients.

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