Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature

Fakhri, Bita; Lim, Kian-Huat

doi:10.21037/jgo.2016.11.01

Cited by 21 publications

(19 citation statements)

References 31 publications

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“…Next, we focused on selected genes with known relevance for tumor initiation and progression as well as tumor suppressive function (Figure 4A). In this analysis and in accordance with the human counterpart, MLH1 -/- -associated tumors harbor additional mutations in PIK3CA , BRAF and/or KRAS and ERBB3 (16). Therefore, we created an oncoprint of the non-synonymous alterations in this selected gene set (Figure 4A).…”

Section: Resultssupporting

confidence: 70%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

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28 29 Abbreviations: CMMR-D -constitutional mismatch repair deficiency, cMS -coding 30 microsatellite, MB -Megabase, MMR -mismatch repair, MMR-D -mismatch repair 31 deficiency, TMB -tumor mutational burden, GIT -gastrointestinal tumor, SNV -single 32 nucleotide variant, WES -whole exome sequencing 33 34 Keywords: Tumor mutational burden, exclusive/ shared mutations, predicted tumor antigens Mutations in MLH1 -/tumors 3 35Abstract 36 MLH1 knock out mice represent a preclinical model that resembles features of the human 37 counterpart. As these mice develop mismatch repair deficient (MMR-D) neoplasias in a 38 sequential twin-peaked manner (first lymphomas, then gastrointestinal tumors) we aimed at 39 identification of the underlying molecular mechanisms. Using whole-exome sequencing, we 40 focused on (I) shared and (II) mutually exclusive mutations and described the processes of 41 ongoing mutational events in tumor-derived cultures. 42 A heterogeneous genetic landscape was found, with few mutations shared among different 43 neoplasias (ARID1A and IDH2). Mutations in tumor suppressor genes SMAD4 and POLE 44 were mutually exclusive in lymphomas, most likely contributing to a more aggressive in vivo 45 phenotype. Comparing the mutational profile of selected primary tumors and their 46 corresponding cell line upon in vitro culture revealed continuous increased numbers of 47 somatic gene mutations. The same was true for coding microsatellite mutations in selected 48 MMR-D target genes, showing a gradual increase during in vitro passage. With respect to this 49 latter type of mutations, partial overlap was detectable, yet recognizing shared vaccination 50 antigens. The two most promising candidates are AKT3, a RAC-gamma serine/threonine-51 protein kinase with relevance in maintenance of cellular homeostasis and the endonuclease 52 ERCC5 (Excision Repair 5), involved in DNA excision repair. 53 Novel results of a comparison between spontaneously developing lymphomas and 54 gastrointestinal tumors as models for MMR-D driven tumorigenesis are reported. In addition 55 to identification of ARID1A as a potentially causative mutation hotspot, our comprehensive 56 characterization of the mutational signature is a starting point for immune-based approaches 57 to therapy. 58 59 Mutations in MLH1 -/tumors 4 60 Author Summary 61 This study describes the mutational spectrum of MLH1 -/--associated tumors, spontaneously 62 developing in mice. While these tumors arise at the bottom of the same germline mutation, 63 the clinical presentations as well as resulting molecular alterations are heterogeneous, and 64 thus likely being directly linked. Highly aggressive lymphomas, developing early in life are 65 ultra-hypermutated and harbor mutations in tumor suppressor genes SMAD4 and POLE. 66 Gastrointestinal tumors develop later in life and show different mutations. By performing in-67 depth whole exome sequencing analysis, we here identified for the first time a common 68 mutational hotspot. ARID1A constitutes a potentially causative mutati...

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Section: Resultssupporting

confidence: 70%

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Gladbach

Wiegele

Hamed

et al. 2019

Preprint

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“…A large number of biomarkers involved in transcriptional, and post-transcriptional regulation via methylation and phosphorylation, have been implicated in cancer development ( Blee, Gray & Brook, 2015 ). However, the findings related to GC are not consistent, and specific targets for the diagnosis and treatment of GC require confirmation ( Fakhri & Lim, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of hub genes and potential molecular mechanisms in gastric cancer by integrated bioinformatics analysis

Cao

Chen

Zhang

et al. 2018

PeerJ

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ObjectiveGastric cancer (GC) is the fourth most common cause of cancer-related deaths in the world. In the current study, we aim to identify the hub genes and uncover the molecular mechanisms of GC.MethodsThe expression profiles of the genes and the miRNAs were extracted from the Gene Expression Omnibus database. The identification of the differentially expressed genes (DEGs), including miRNAs, was performed by the GEO2R. Database for Annotation, Visualization and Integrated Discovery was used to perform GO and KEGG pathway enrichment analysis. The protein–protein interaction (PPI) network and miRNA-gene network were constructed using Cytoscape software. The hub genes were identified by the Molecular Complex Detection (MCODE) plugin, the CytoHubba plugin and miRNA-gene network. Then, the identified genes were verified by Kaplan–Meier plotter database and quantitative real-time PCR (qRT-PCR) in GC tissue samples.ResultsA total of three mRNA expression profiles (, and ) were downloaded from the Gene Expression Omnibus (GEO) database, including 69, 20 and 27cases separately. A total of 120 overlapped upregulated genes and 246 downregulated genes were identified. The majority of the DEGs were enriched in extracellular matrix organization, collagen catabolic process, collagen fibril organization and cell adhesion. In addition, three KEGG pathways were significantly enriched, including ECM-receptor interaction, protein digestion and absorption, and the focal adhesion pathways. In the PPI network, five significant modules were detected, while the genes in the modules were mainly involved in the ECM-receptor interaction and focal adhesion pathways. By combining the results of MCODE, CytoHubba and miRNA-gene network, a total of six hub genes including COL1A2, COL1A1, COL4A1, COL5A2, THBS2 and ITGA5 were chosen. The Kaplan–Meier plotter database confirmed that higher expression levels of these genes were related to lower overall survival, except for COL5A2. Experimental validation showed that the rest of the five genes had the same expression trend as predicted.ConclusionIn conclusion, COL1A2, COL1A1, COL4A1, THBS2 and ITGA5 may be potential biomarkers and therapeutic targets for GC. Moreover, ECM-receptor interaction and focal adhesion pathways play significant roles in the progression of GC.

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“…Therefore, there is a great interest in deciphering the molecular pathways associated with its progression and prognosis. Environment and lifestyles are general risk factors for GC, but interaction of diet with multiple genetic and epigenetic alterations also occur during GC development [ 2 , 3 , 4 , 5 ]. Proteomics provided consistent information in revealing proteome alterations associated with GC, dissected some of the mechanisms underlying gastric cancerogenesis, and enabled the identification of several diagnostic, prognostic, and predictive biomarkers [ 6 , 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Quantitative Proteomic Approach Targeted to Fibrinogen β Chain in Tissue Gastric Carcinoma

Repetto

Maiero

Magris

et al. 2018

IJMS

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Elevated plasma fibrinogen levels and tumor progression in patients with gastric cancer (GC) have been largely reported. However, distinct fibrinogen chains and domains have different effects on coagulation, inflammation, and angiogenesis. The aim of this study was to characterize fibrinogen β chain (FGB) in GC tissues. Retrospectively we analyzed the data of matched pairs of normal (N) and malignant tissues (T) of 28 consecutive patients with GC at diagnosis by combining one- and two-dimensional electrophoresis (1DE and 2DE) with immunoblotting and mass spectrometry together with two-dimensional difference in gel electrophoresis (2D-DIGE). 1DE showed bands of the intact FGB at 50 kDa and the cleaved forms containing the fragment D at ~37–40 kDa, which corresponded to 19 spots in 2DE. In particular, spot 402 at ~50 kDa and spots 526 and 548 at ~37 kDa were of interest by showing an increased expression in tumor tissues. A higher content of spot 402 was associated with stomach antrum, while spots 526 and 548 amounts correlated with corpus and high platelet count (>208 × 109/L). The quantification of FGB and cleaved products may help to further characterize the interconnections between GC and platelet/coagulation pathways.

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Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature

Cited by 21 publications

References 31 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Identification of hub genes and potential molecular mechanisms in gastric cancer by integrated bioinformatics analysis

Quantitative Proteomic Approach Targeted to Fibrinogen β Chain in Tissue Gastric Carcinoma

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Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature

Cited by 21 publications

References 31 publications

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1-/-mice

Identification of hub genes and potential molecular mechanisms in gastric cancer by integrated bioinformatics analysis

Quantitative Proteomic Approach Targeted to Fibrinogen β Chain in Tissue Gastric Carcinoma

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Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice

Unraveling the heterogeneous mutational signature of spontaneously developing tumors in MLH1^-/-mice