Abstract 2721: Prospective whole exome and whole transcriptome sequencing of hematologic cancers for biomarker-driven treatment : Preliminary results of a randomized pragmatic clinical trial

2017 ◽  
Author(s):  
Sanga Kim ◽  
Ryul Kim ◽  
Youngil Koh ◽  
Choong Hyun Sun ◽  
Hogune Im ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Transcriptome Sequencing ◽  
Pragmatic Clinical Trial ◽  
Preliminary Results ◽  
Whole Exome ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

scholarly journals Whole-exome and whole-transcriptome sequencing of canine mammary gland tumors

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Ka-Kyung Kim ◽  
Byung-Joon Seung ◽  
Dohyun Kim ◽  
Hee-Myung Park ◽  
Sejoon Lee ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Transcriptome Sequencing ◽  
Mammary Gland Tumors ◽  
Whole Exome ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome ◽  
Canine Mammary Gland

Bladder tumor metabolic alterations in response to IFNα gene therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 468-468
Author(s):  
Tanner Miest ◽  
Anirban P Mitra ◽  
Vikram M Narayan ◽  
Colin P.N. Dinney ◽  
Sharada Mokkapati
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Bladder Cancer ◽  
Transcriptome Sequencing ◽  
Lactate Production ◽  
Poly I:C ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

468 Background: Intravesical interferon-alpha (IFNα) gene therapy with Nadofaragene firadenovec has shown clinical efficacy in patients with non-muscle invasive bladder cancer (NMIBC) in a phase III clinical trial, highlighting the therapeutic potential of this approach in a disease with significant unmet clinical need. Optimizing the clinical efficacy of IFNα gene therapy requires an understanding of the underlying therapeutic mechanisms. Here, we investigate the impact of IFNα gene therapy on tumor metabolism using in vitro and orthotopic murine preclinical models and clinical trial data to elucidate mechanisms of tumor resistance and identify predictive biomarkers. Methods: In vitro murine bladder cancer cell lines treated with recombinant IFNα (rIFNα) and lentiviral IFNα (LV-IFNα) were analyzed by whole-transcriptome sequencing, glucose uptake, and lactate production. Preclinical murine bladder cancer models were treated with LV-IFNα (orthotopic tumor model) or Poly(I:C) (flank tumor model), a potent IFN inducer. Disease response was monitored by in vivo real-time luciferase imaging. Tumors were harvested and whole-transcriptome sequencing performed to assess effects of IFNα therapy on tumor metabolism and lipidomics. Lipidomic profiling was performed on patient urine samples from a phase II clinical trial of intravesical Nadofaragene firadenovec (7 clinical responders and 6 non-responders) to assess for clinically-relevant differences in lipid metabolism. Results: Following IFNα therapy in vitro and in murine orthotopic bladder cancer models, we identified downregulation of genes involved in fatty acid synthesis and upregulation of genes involved in glycolysis by whole-transcriptome sequencing. This was confirmed by higher glucose uptake and lactate production by IFNα-treated cells in vitro. These findings were recapitulated in whole-transcriptome sequencing data of human bladder tumors treated with intravesical Nadofaragene firadenovec. Lipidomics performed on murine MB49 tumors treated with poly(I:C) identified 79 upregulated lipids, including phosphotidyl choline, spingomyelin and phosphatidyl ethanolamine, and 12 downregulated lipids, notably the cardiolipin class. Lipidomics performed on patient urine samples collected pre- and post-treatment with intravesical Nadofaragene firadenovec detected >592 lipids with distinct expression profiles differentiating clinical responders and non-responders at both timepoints. Conclusions: We describe novel modulation of glucose and lipid metabolism by bladder tumor cells in response to IFNα gene therapy. These metabolic changes were reproducible across in vitro, in vivo and clinical trial studies and improve our mechanistic understanding of IFNα gene therapy, identify tumor escape pathways targetable with combination therapy regimens, and identify a new class of biomarkers for predicting clinical response of NMIBC to IFNα gene therapy.

scholarly journals Clonotypic heterogeneity in cutaneous T-cell lymphoma (mycosis fungoides) revealed by comprehensive whole-exome sequencing

2019 ◽  
Vol 3 (7) ◽  
pp. 1175-1184 ◽  
Author(s):  
Aishwarya Iyer ◽  
Dylan Hennessey ◽  
Sandra O’Keefe ◽  
Jordan Patterson ◽  
Weiwei Wang ◽  
...  
Keyword(s):  
T Cell ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mycosis Fungoides ◽  
Transcriptome Sequencing ◽  
Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Whole Exome ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

Abstract Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, is believed to represent a clonal expansion of a transformed skin-resident memory T cell. T-cell receptor (TCR) clonality (ie, identical sequences of rearranged TCRα, TCRβ, and TCRγ), the key premise of this hypothesis, has been difficult to document conclusively because malignant cells are not readily distinguishable from the tumor-infiltrating reactive lymphocytes that contribute to the TCR clonotypic repertoire of MF. Here, we have successfully adopted targeted whole-exome sequencing (WES) to identify the repertoire of rearranged TCR genes in tumor-enriched samples from patients with MF. Although some of the investigated MF biopsies had the expected frequency of monoclonal rearrangements of TCRγ corresponding to that of tumor cells, the majority of the samples presented multiple TCRγ, TCRα, and TCRβ clonotypes by WES. Our findings are compatible with the model in which the initial malignant transformation in MF does not occur in mature memory T cells but rather at the level of T-lymphocyte progenitors before TCRβ or TCRα rearrangements. We have also shown that WES can be combined with whole-transcriptome sequencing in the same sample, which enables comprehensive characterization of the TCR repertoire in relation to tumor content. WES/whole-transcriptome sequencing might be applicable to other types of T-cell lymphomas to determine clonal dominance and clonotypic heterogeneity in these malignancies.

Mammary-type Myofibroblastoma with Leiomyomatous Differentiation: A Rare Variant with Potential Pitfalls

2021 ◽  
pp. 106689692110313
Author(s):  
Alexander M. Strait ◽  
Julia A. Bridge ◽  
Anthony J. Iafrate ◽  
Marilyn M. Li ◽  
Feng Xu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Transcriptome Sequencing ◽  
Smooth Muscle Actin ◽  
The Body ◽  
Muscle Actin ◽  
Mature Adipose Tissue ◽  
Spindle Cells ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

Myofibroblastoma is a rare, benign stromal tumor with a diverse morphologic spectrum. Mammary-type myofibroblastoma (MTMF) is the extra-mammary counterpart of this neoplasm and its occurrence throughout the body has become increasingly recognized. Similar morphologic variations of MTMF have now been described which mirror those seen in the breast. We describe a case of intra-abdominal MTMF composed of short fascicles of eosinophilic spindle cells admixed with mature adipose tissue. The spindle cells stained diffusely positive for CD34, desmin, smooth muscle actin, and h-caldesmon by immunohistochemistry. Concurrent loss of RB1 (13q14) and 13q34 loci were confirmed by fluorescence in situ hybridization whereas anchored multiplex PCR and whole transcriptome sequencing did not reveal any pathognomonic fusions suggesting an alternative diagnosis. To the best of our knowledge this is the first documented case of leiomyomatous variant of MTMF.

The prognosis of gastric adenocarcinoma depends on the crosstalk between immune profiles and tumor genomic alterations.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4035-4035
Author(s):  
Deqiang Wang ◽  
Xiaofeng Chen ◽  
Yaping Xu ◽  
Yuange He ◽  
Lifeng Li ◽  
...  
Keyword(s):  
Gastric Adenocarcinoma ◽  
Transcriptome Sequencing ◽  
Clonal Expansion ◽  
Genomic Alterations ◽  
M1 Macrophages ◽  
Mutual Correlation ◽  
Cell Counts ◽  
M1 Macrophage ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

4035 Background: Gastric adenocarcinoma (GAC) is with a complex microenvironment of tumor cells. A better understanding of the immune landscape of GACs may lead to the improved treatment strategies with ICIs. Methods: To determine whether the molecular characteristics can serve in prognostic stratification of GACs, tumor tissue and blood samples were collected from 231 GAC patients. The median follow-up time was 34 months. The TCR profile was determined by TCR-β CDR3 sequencing while mutation and gene expression profiles were determined by whole exon and whole transcriptome sequencing, respectively. Tumour-infiltrating immune cells were characterized using immunofluorescence (IF) staining. Results: The results showed the OS of patients with high levels of TCR clonality (TCR clonal expansion) was significantly improved compared with patients with low levels (HR = 1.80 and 2.22, p = 0.022 and 0.008, respectively) in the whole group and in the subgroup of patients with stages IB to III disease. Furthermore, low local clonality was an independent risk factor for OS (adjusted-HR = 1.68 and 1.95, p = 0.049 and 0.029, respectively). Thus, TCR clonal expansion in tumour tissue had a strong prognostic value for GAC patients, independent of clinicopathological factors. Based on whole exon and whole transcriptome sequencing, RNF43/FBXW7/ARID2 mutations and local TCR clonality jointly impacted prognosis (p < 0.001), and functional changes in corresponding Wnt pathway/Notch pathway/SWI/SNF complex characterized a GAC subset with enhanced tumour immunogenicity and TCR clonal expansion. TCR CDR3 sequence similarity comparisons yielded clusters of TCR clones of likely similar functions. The most expansive TCR clusters negatively correlated with the percentage of subclonal mutations (Pearson r = -0.8183, p < 0.001), indicating that tumors with less genomic heterogeneity might induce a greater immune response. By IF staining and mutual correlation analysis, only M1 macrophages showed a significant positive correlation with local TCR clonality for epithelia, stroma, and total cell counts. Tumors were categorized according to the density of M1 macrophages, M1 macrophage infiltrated subtype was associated with favorable OS (p = 0.040 and 0.043) and its combination with the local TCR clonality improved prognosis stratification (p < 0.001). Finally, the scoring by local TCR clonality, RNF43/FBXW7/ARID2 mutations and M1 infiltration determined the best prognosis (p < 0.001). Conclusions: TCR profiles were associated with genomic alterations and may serve as a prognostic biomarker for GACs. A multi-omic model including TCR profiles might produce an improved stratification for treatments and outcomes.

Analysis of mRNAs and ncRNAs and Prediction Competing Endogenous RNA Networks in Colorectal Cancer Chemo-Resistance by Whole-Transcriptome Sequencing

2020 ◽  
Author(s):  
Fei Yao ◽  
Chuanren Zhou ◽  
Qiyou Huang ◽  
Xiaoying Huang ◽  
Jie Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Transcriptome Sequencing ◽  
Regulatory Networks ◽  
Parental Cell ◽  
Resistant Cell ◽  
Competing Endogenous Rna ◽  
Whole Transcriptome Sequencing ◽  
Whole Transcriptome

Abstract Background: Chemo-resistance is a major clinical obstacle to the treatment of colorectal cancer (CRC), mRNAs and non-coding RNAs (ncRNAs) have been reported to modulate the development of chemo-resistance. However, the profiles of mRNAs and ncRNAs as well as competing endogenous RNA (ceRNA) networks in CRC chemo-resistance are still unclear, and whether different drug resistance of CRC have the same mechanisms also needs to be explored. This study aims to uncover the expression of mRNAs and ncRNAs in parental cell lines and different chemo-resistant cell lines, and construct ceRNA regulatory networks by whole-transcriptome sequencing.Methods: The expression of mRNAs and ncRNAs in parental cell lines and drug-resistant cell lines were identified by whole-transcriptome sequencing and bioinformatics methods.Results: A total of 1779 mRNAs, 64 miRNAs, 11 circRNAs and 295 lncRNAs were common differentially expressed in two different chemo-resistant cell lines when compared with the control. In addition, 5,767 lncRNA-miRNA-mRNA relationship pairs and 47 circRNA-miRNA-mRNA pathways were constructed according to ceRNA regulatory rules, in which AC109322.2-hsa-miR-371a-5p-BTNL3 and hsacirc_027876-hsa-miR-582-3p-FREM1 were identified as the most potential ceRNA networks involved in drug resistance to CRC. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of two ceRNA regulatory networks showed that the TNF signaling pathway may be crucial in the process of CRC drug resistance.Conclusions: A large number of mRNAs and ncRNAs in chemo-resistant cell lines were different expressed, which may play pivotal roles in development of drug resistance through the ceRNA regulatory network. This study may improve our understanding of the underlying mechanisms and provide a promising therapeutic strategy for CRC chemo-resistance.

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