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      The APC waiver has been extended to also apply to manuscripts submitted until March 31, 2024.

      To submit to the journal, please click here.

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      Immune landscape in APC and TP53 related tumor microenvironment in colon adenocarcinoma: A bioinformatic analysis

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          Abstract

          Introduction

          APC and TP53 are the two most regularly mutated genes in colon adenocarcinoma (COAD), especially in progressive malignancies and antitumoral immune response. The current bioinformatics analysis investigates the APC and TP53 gene expression profile in colon adenocarcinoma as a prognostic characteristic for survival, particularly concentrating on the correlated immune microenvironment.

          Methods

          Clinical and genetic data of colon cancer and normal tissue samples were obtained from The Cancer Genome Atlas (TCGA)-COAD and Genotype-Tissue Expression (GTEx) online databases, respectively. The genetic differential expressions were analyzed in both groups via the one-way ANOVA test. Kaplan–Meier survival curves were applied to estimate the overall survival (OS). P < 0.05 was fixed as statistically significant. On Tumor Immune Estimation Resource and Gene Expression Profiling Interactive Analysis databases, the linkage between immune cell recruitment and APC and TP53 status was assessed through Spearman's correlation analysis.

          Results

          APC and TP53 were found mutated in 66.74% and 85.71% of the 454 and 7 TCGA-COAD patients in colon and rectosigmoid junction primary sites, respectively with a higher log2-transcriptome per million reads compared to the GTEx group (318 samples in sigmoid and 368 samples in transverse). Survival curves revealed a worse significant OS for the high-APC and TP53 profile colon. Spearman's analysis of immune cells demonstrated a strong positive correlation between the APC status and infiltration of T cell CD4+, T cell CD8+, NK cell, and macrophages and also a positive correlation between status and infiltration of T cell CD4+, T cell CD8+.

          Conclusions

          APC and TP53 gene mutations prevail in colon cancer and are extremely associated with poor prognosis and shortest survival. The infiltrating T cell CD4+, T cell CD8+, NK cell, and macrophages populate the colon microenvironment and regulate the mechanisms of tumor advancement, immune evasion, and sensitivity to standard chemotherapy. More comprehensive research is needed to demonstrate these results and turn them into new therapeutic outlooks.

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          Most cited references51

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          Global Burden of 5 Major Types Of Gastrointestinal Cancer

          There were an estimated 4.8 million new cases of gastrointestinal (GI) cancers and 3.4 million related deaths, worldwide, in 2018. GI cancers account for 26% of the global cancer incidence and 35% of all cancer-related deaths. We investigated the global burden from the 5 major GI cancers, as well as geographic and temporal trends in cancer-specific incidence and mortality.
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            Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

            Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.
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              Multiple Roles of APC and its Therapeutic Implications in Colorectal Cancer.

              Adenomatous polyposis coli (APC) is widely accepted as a tumor suppressor gene highly mutated in colorectal cancers (CRC). Mutation and inactivation of this gene is a key and early event almost uniquely observed in colorectal tumorigenesis. Alterations in the APC gene generate truncated gene products, leading to activation of the Wnt signaling pathway and deregulation of multiple other cellular processes. It has been a mystery why most patients with CRC retain a truncated APC protein, but accumulating evidence suggest that these C terminally truncated APC proteins may have gain of function properties beyond the well-established loss of tumor suppressive function. Here, we will review the evidence for both the loss of function and the gain of function of APC truncations and how together they contribute to CRC initiation and progression.
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                Author and article information

                Contributors
                Journal
                1886
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó (Budapest )
                2062-509X
                2062-8633
                12 March 2024
                Affiliations
                [1 ] Department of Chemistry, Lahijan Branch, Islamic Azad University , Lahijan, Iran
                [2 ] Medical Biology Research Center, Kermanshah University of Medical Sciences , Kermanshah, Iran
                [3 ] Guilan Road Trauma Research Center, Trauma Institute, Guilan University of Medical Sciences , Rasht, Iran
                Author notes
                [* ]Corresponding author. E-mail: so.vahidii@ 123456gmail.com
                [** ]Corresponding author. E-mail: a_a_hormoz@ 123456yahoo.com
                Author information
                https://orcid.org/0000-0002-1794-0563
                https://orcid.org/0000-0003-2701-9943
                Article
                10.1556/1886.2024.00015
                fb01e05b-a3da-46f7-891d-fd31e35438a7
                © 2024 The Author(s)

                Open Access statement. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and reproduction in any medium for non-commercial purposes, provided the original author and source are credited, a link to the CC License is provided, and changes – if any – are indicated.

                History
                : 02 February 2024
                : 22 February 2024
                Page count
                Figures: 6, Tables: 1, Equations: 0, References: 51, Pages: 12

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                APC,colon adenocarcinoma,TP53,The Cancer Genome Atlas

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