Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression‐based study

Abstract Background Since interferon regulatory factor (IRF) family functions in immune response to viral infection, its role in colorectal cancer (CRC) has not been inspected before. This study tries to investigate members of IRF family using bioinformatics approaches in aspect of differential expressions, biological function, tumor immune infiltration and clinical prognostic value for patients with CRC. Methods Transcriptome profiles data, somatic mutations and clinical information of CRC were obtained from COAD/READ dataset of The Cancer Genome Atlas (TCGA) as a training set. Gene expression data (GSE17536 and GSE39582) were downloaded from the Gene Expression Omnibus as a validating set. A random forest algorithm was used to score the risk for every case. Analyzing gene and function enrichment, constructing protein–protein interaction and noncoding RNA network, identifying hub-gene, characterizing tumor immune infiltration, evaluating differences in tumor mutational burden (TMB) and sensitivity to chemotherapeutics or immunotherapy were performed by a series of online tools and R packages. Immunohistochemical (IHC) examinations were carried out validation in tissue samples. Results Principal-component analysis (PCA) suggested that the transcript expression levels of nine members of IRF family differed between normal colorectum and CRC. The risk score constructed by IRF family not only acted as an independent factor for predicting survival in CRC patients with different biological processes, signaling pathways and TMB, but also indicated different immunotherapy response with diverse immune and stromal cells infiltration. IRF3 and IRF7 were upregulated in CRC and suggested a shorter survival time in patients with CRC. Differentially expressed members of IRF family exhibited varying degrees of immune cell infiltration. IHC analysis showed a positive association between IRF3 and IRF7 expression and tumor-infiltrating immune cells, including CD4+ T cell and CD68+ macrophages. Conclusions On account of differential expression, IRF family members can help to predict both response to immunotherapy and clinical prognosis of patients with CRC. Our bioinformatic investigation not only gives a preliminary picture of the genetic features as well as tumor microenvironment, but it may provide a clue for further experimental exploration and verification on IRF family members in CRC.

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Computational Tumor Infiltration Phenotypes Enable the Spatial and Genomic Analysis of Immune Infiltration in Colorectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.552331 ◽

2021 ◽

Vol 11 ◽

Author(s):

Henrik Failmezger ◽

Natalie Zwing ◽

Achim Tresch ◽

Konstanty Korski ◽

Fabian Schmich

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Computational Method ◽

The Cancer Genome Atlas ◽

Point Pattern Analysis ◽

Point Pattern ◽

Base Line ◽

Tumor Infiltration ◽

Durable Response ◽

Immune Infiltration

Cancer immunotherapy has led to significant therapeutic progress in the treatment of metastatic and formerly untreatable tumors. However, drug response rates are variable and often only a subgroup of patients will show durable response to a treatment. Biomarkers that help to select those patients that will benefit the most from immunotherapy are thus of crucial importance. Here, we aim to identify such biomarkers by investigating the tumor microenvironment, i.e., the interplay between different cell types like immune cells, stromal cells and malignant cells within the tumor and developed a computational method that determines spatial tumor infiltration phenotypes. Our method is based on spatial point pattern analysis of immunohistochemically stained colorectal cancer tumor tissue and accounts for the intra-tumor heterogeneity of immune infiltration. We show that, compared to base-line models, tumor infiltration phenotypes provide significant additional support for the prediction of established biomarkers in a colorectal cancer patient cohort (n = 80). Integration of tumor infiltration phenotypes with genetic and genomic data from the same patients furthermore revealed significant associations between spatial infiltration patterns and common mutations in colorectal cancer and gene expression signatures. Based on these associations, we computed novel gene signatures that allow one to predict spatial tumor infiltration patterns from gene expression data only and validated this approach in a separate dataset from the Cancer Genome Atlas.

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Tumor immune infiltration estimated from gene expression profiles predicts colorectal cancer relapse

OncoImmunology ◽

10.1080/2162402x.2020.1862529 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1862529

Author(s):

Yasmin Kamal ◽

Dennis Dwan ◽

Hannah J. Hoehn ◽

Rebeca Sanz-Pamplona ◽

M. Henar Alonso ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Immune Infiltration ◽

Cancer Relapse

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Polymorphism of the MTHFR Gene is Associated with Altered Gene Expression in Colorectal Cancer

Endoscopy ◽

10.1055/s-2004-824986 ◽

2004 ◽

Vol 36 (05) ◽

Author(s):

K Collins ◽

GA Doherty ◽

MR Sweeney ◽

SM Byrne ◽

AA Aftab ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Mthfr Gene ◽

Altered Gene Expression ◽

Altered Gene

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Gene Expression of Survivin in Colorectal Cancer

International Journal of Scientific and Research Publications (IJSRP) ◽

10.29322/ijsrp.9.04.2019.p8874 ◽

2019 ◽

Vol 9 (4) ◽

pp. p8874

Author(s):

Abdel-Aziz A.F. ◽

El-Hussiny M.A.B. ◽

Bakr N.M. ◽

Mehrez H.A.

Keyword(s):

Gene Expression ◽

Colorectal Cancer

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Faculty Opinions recommendation of Clinical value of prognosis gene expression signatures in colorectal cancer: a systematic review.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717964771.793469145 ◽

2013 ◽

Author(s):

Yiqian Nancy You ◽

Brian Keith Bednarski

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Systematic Review ◽

Clinical Value ◽

Gene Expression Signatures

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37 Monitoring the evolution of inflammatory bowel disease (IBD) in pediatric and adult cohorts of patients to identify biomarkers to predict cancer risk

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0037 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A38-A38

Author(s):

Shilpa Ravindran ◽

Heba Sidahmed ◽

Harshitha Manjunath ◽

Rebecca Mathew ◽

Tanwir Habib ◽

...

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Colorectal Cancer ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Mesenchymal Transition ◽

Increased Risk ◽

Hamad Medical Corporation ◽

Inflammatory Bowel ◽

Left And Right

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

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Increased Expression of VANGL1 is Predictive of Lymph Node Metastasis in Colorectal Cancer: Results from a 20-Gene Expression Signature

Journal of Personalized Medicine ◽

10.3390/jpm11020126 ◽

2021 ◽

Vol 11 (2) ◽

pp. 126

Author(s):

Noshad Peyravian ◽

Stefania Nobili ◽

Zahra Pezeshkian ◽

Meysam Olfatifar ◽

Afshin Moradi ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Lymph Node ◽

Lymph Node Metastasis ◽

Candidate Genes ◽

Case Series ◽

Gene Expression Signature ◽

Gene Panel ◽

Expression Levels ◽

Node Metastasis

This study aimed at building a prognostic signature based on a candidate gene panel whose expression may be associated with lymph node metastasis (LNM), thus potentially able to predict colorectal cancer (CRC) progression and patient survival. The mRNA expression levels of 20 candidate genes were evaluated by RT-qPCR in cancer and normal mucosa formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients. Receiver operating characteristic curves were used to evaluate the prognosis performance of our model by calculating the area under the curve (AUC) values corresponding to stage and metastasis. A total of 100 FFPE primary tumor tissues from stage I–IV CRC patients were collected and analyzed. Among the 20 candidate genes we studied, only the expression levels of VANGL1 significantly varied between patients with and without LNMs (p = 0.02). Additionally, the AUC value of the 20-gene panel was found to have the highest predictive performance (i.e., AUC = 79.84%) for LNMs compared with that of two subpanels including 5 and 10 genes. According to our results, VANGL1 gene expression levels are able to estimate LNMs in different stages of CRC. After a proper validation in a wider case series, the evaluation of VANGL1 gene expression and that of the 20-gene panel signature could help in the future in the prediction of CRC progression.

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Metastatic heterogeneity of the consensus molecular subtypes of colorectal cancer

npj Genomic Medicine ◽

10.1038/s41525-021-00223-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Peter W. Eide ◽

Seyed H. Moosavi ◽

Ina A. Eilertsen ◽

Tuva H. Brunsell ◽

Jonas Langerud ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Principal Components ◽

Prognostic Value ◽

Tumor Heterogeneity ◽

Molecular Subtypes ◽

R Package ◽

Data Set ◽

Primary Tumors ◽

External Data

AbstractGene expression-based subtypes of colorectal cancer have clinical relevance, but the representativeness of primary tumors and the consensus molecular subtypes (CMS) for metastatic cancers is not well known. We investigated the metastatic heterogeneity of CMS. The best approach to subtype translation was delineated by comparisons of transcriptomic profiles from 317 primary tumors and 295 liver metastases, including multi-metastatic samples from 45 patients and 14 primary-metastasis sets. Associations were validated in an external data set (n = 618). Projection of metastases onto principal components of primary tumors showed that metastases were depleted of CMS1-immune/CMS3-metabolic signals, enriched for CMS4-mesenchymal/stromal signals, and heavily influenced by the microenvironment. The tailored CMS classifier (available in an updated version of the R package CMScaller) therefore implemented an approach to regress out the liver tissue background. The majority of classified metastases were either CMS2 or CMS4. Nonetheless, subtype switching and inter-metastatic CMS heterogeneity were frequent and increased with sampling intensity. Poor-prognostic value of CMS1/3 metastases was consistent in the context of intra-patient tumor heterogeneity.

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The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer

Cell & Bioscience ◽

10.1186/s13578-021-00583-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Zhihao Fang ◽

Yiqiu Hu ◽

Jinhui Hu ◽

Yanqin Huang ◽

Shu Zheng ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Nuclear Export ◽

Messenger Rna ◽

Regulatory Proteins ◽

Biological Processes ◽

The Past ◽

Common Cancer ◽

Potential Applications ◽

Regulated Gene Expression

AbstractAs the predominant modification in RNA, N6-methyladenosine (m6A) has attracted increasing attention in the past few years since it plays vital roles in many biological processes. This chemical modification is dynamic, reversible and regulated by several methyltransferases, demethylases and proteins that recognize m6A modification. M6A modification exists in messenger RNA and affects their splicing, nuclear export, stability, decay, and translation, thereby modulating gene expression. Besides, the existence of m6A in noncoding RNAs (ncRNAs) could also directly or indirectly regulated gene expression. Colorectal cancer (CRC) is a common cancer around the world and of high mortality. Increasing evidence have shown that the changes of m6A level and the dysregulation of m6A regulatory proteins have been implicated in CRC carcinogenesis and progression. However, the underlying regulation laws of m6A modification to CRC remain elusive and better understanding of these mechanisms will benefit the diagnosis and therapy. In the present review, the latest studies about the dysregulation of m6A and its regulators in CRC have been summarized. We will focus on the crucial roles of m6A modification in the carcinogenesis and development of CRC. Moreover, we will also discuss the potential applications of m6A modification in CRC diagnosis and therapeutics.

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