scholarly journals Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 510 ◽  
Author(s):  
Koki Nakamura ◽  
Yuji Urabe ◽  
Kenichi Kagemoto ◽  
Ryo Yuge ◽  
Ryohei Hayashi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gastric Mucosa ◽  
Sequence Data ◽  
Important Change ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Non Invasive ◽  
Fresh Frozen ◽  
Genomic Characterization

Background and aims: Recent genomic characterization of gastric cancer (GC) by sequencing has revealed a large number of cancer-related genes. Research to characterize the genomic landscape of cancer has focused on established invasive cancer to develop biomarkers for therapeutic or diagnostic targets, and nearly all GC reports have been about advanced GC. The aim of this study is to identify recurrently mutated genes in non-invasive GC and, in particular, the driver mutations that are associated with the development of GC. Methods and results: We performed whole-exome sequencing of 19 fresh frozen specimens of differentiated-type non-invasive GC and targeted sequencing for 168 genes of 30 formalin-fixed paraffin-embedded archival specimens of differentiated-type non-invasive GC. We found that TP53 and LRP1 are significantly associated with non-invasive GC. It has been reported that LPR1 is associated with CagA autophagy in gastric mucosa. Therefore, we downloaded RNA sequence data for gastric cancer from the The Cancer Genome Atlas (TCGA) Genomic Data Commons Data Portal and examined the differences in LRP1 gene expression levels. The expression level was significantly lower in cases without LRP1 mutation than in cases with LRP1 mutation. Based on these results, fluorescent immunostaining for CagA was performed for 49 of the above samples to evaluate CagA accumulation within the cancerous tissue. Accumulation of CagA was significantly greater when an LRP1 mutation was present than without a mutation. Conclusion: These data suggest that LRP1 mutation is an important change promoting the transformation of gastric mucosa to GC early in the carcinogenesis of cancer.

Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

2020 ◽  
Vol 20 (7) ◽  
pp. 490-500 ◽  
Author(s):  
Justin S. Becker ◽  
Amir T. Fathi
Keyword(s):  
Genome Structure ◽  
Cellular Metabolism ◽  
Standard Of Care ◽  
Competitive Inhibitor ◽  
Driver Mutations ◽  
New Class ◽  
Regulatory Enzymes ◽  
Idh Mutations ◽  
Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

scholarly journals Comprehensive Genomic Characterization Analysis Identifies an Oncogenic Pseudogene RP11-3543B.1 in Human Gastric Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin Chen ◽  
Zhenyao Chen ◽  
Hao Wu ◽  
Xianghua Liu ◽  
Fengqi Nie ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Cells ◽  
Expression Profiling ◽  
The Cancer Genome Atlas ◽  
Human Gastric Cancer ◽  
Gastric Cancer Cells ◽  
Altered Expression ◽  
Genomic Characterization

Background: Gastrointestinal Cancer (GICs) is the most common group of malignancies, and many of its types are the leading causes of cancer related death worldwide. Pseudogenes have been revealed to have critical regulatory roles in human cancers. The objective of this study is to comprehensive characterize the pseudogenes expression profiling and identify key pseudogenes in the development of gastric cancer (GC).Methods: The pseudogenes expression profiling was analyzed in six types of GICs cancer from The Cancer Genome Atlas RNA-seq data to identify GICs cancer related pseudogenes. Meanwhile, the genomic characterization including somatic alterations of pseudogenes was analyzed. Then, CCK8 and colony formation assays were performed to evaluate the biological function of RP11-3543B.1 and miR-145 in gastric cancer cells. The mechanisms of pseudogene RP11-3543B.1 in GC cells were explored via using bioinformatics analysis, next generation sequencing and lucifarese reporter assay.Results: We identified a great number of pseudogenes with significantly altered expression in GICs, and some of these pseudogenes expressed differently among the six cancer types. The amplification or deletion in the pseudogenes-containing loci involved in the alterations of pseudogenes expression in GICs. Among these altered pseudogenes, RP11-3543B.1 is significantly upregulated in gastric cancer. Down-regulation of RP11-3543B.1 expression impaired GC cells proliferation both in vitro and in vivo. RP11-3543B.1 exerts oncogene function via targeting miR-145-5p to regulate MAPK4 expression in gastric cancer cells.Conclusion: Our study reveals the potential of pseudogenes expression as a new paradigm for investigating GI cancer tumorigenesis and discovering prognostic biomarkers for patients.

scholarly journals Genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations

Oncotarget ◽  
2016 ◽  
Vol 7 (40) ◽  
pp. 65485-65503 ◽  
Author(s):  
Jean-François Spinella ◽  
Pauline Cassart ◽  
Chantal Richer ◽  
Virginie Saillour ◽  
Manon Ouimet ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Driver Mutations ◽  
Genomic Characterization ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Molecular and Clinical Characterization of a Claudin-Low Subtype of Gastric Cancer

2017 ◽  
pp. 1-10 ◽  
Author(s):  
Tomohiro F. Nishijima ◽  
Jordan Kardos ◽  
Shengjie Chai ◽  
Christof C. Smith ◽  
Dante S. Bortone ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Data Set ◽  
Mesenchymal Transition ◽  
Gene Sets ◽  
Hazard Ratios ◽  
Gene Predictor ◽  
Cancer Genome Atlas

Purpose Claudin-low molecular subtypes have been identified in breast and bladder cancers and are characterized by low expression of claudins, enrichment for epithelial-to-mesenchymal transition (EMT), and tumor-initiating cell (TIC) features. We evaluated whether the claudin-low subtype also exists in gastric cancer. Materials and Methods Four hundred fifteen tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set were clustered on the claudin, EMT, and TIC gene sets to identify claudin-low tumors. We derived a 24-gene predictor that classifies gastric cancer into claudin-low and non–claudin-low subtypes. This predictor was validated with the Asian Cancer Research Group (ACRG) data set. We characterized molecular and clinical features of claudin-low tumors. Results We identified 46 tumors that had consensus enrichment for claudin-low features in TCGA data set. Claudin-low tumors were most commonly diffuse histologic type (82%) and originally classified as TCGA genomically stable (GS) subtype (78%). Compared with GS subtype, claudin-low subtype had significant activation in Rho family of GTPases signaling, which appears to play a key role in its EMT and TIC properties. In the ACRG data set, 28 of 300 samples were classified as claudin-low tumors by the 24-gene predictor and were phenotypically similar to the initially derived claudin-low tumors. Clinically, claudin-low subtype had the worst overall survival. Of note, the hazard ratios that compared claudin-low versus GS subtype were 2.10 (95% CI, 1.07 to 4.11) in TCGA and 2.32 (95% CI, 1.18 to 4.55) in the ACRG cohorts, with adjustment for age and pathologic stage. Conclusion We identified a gastric claudin-low subtype that carries a poor prognosis likely related to therapeutic resistance as a result of its EMT and TIC phenotypes.

scholarly journals Genomic characterization of rare molecular subclasses of hepatocellular carcinoma

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jeffrey S. Damrauer ◽  
Markia A. Smith ◽  
Vonn Walter ◽  
Aatish Thennavan ◽  
Lisle E. Mose ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Primary Liver Cancer ◽  
Progression Free Survival ◽  
The Cancer Genome Atlas ◽  
Mutational Signatures ◽  
Disease Biology ◽  
Cancer Genome Atlas ◽  
Genomic Characterization

AbstractPrimary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.

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