Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 333-333
Author(s):  
Iris Simon ◽  
Paul Roepman ◽  
Andreas Schlicker ◽  
Josep Tabernero ◽  
Ian Majewski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Mutation Frequency ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Classification ◽  
Chemotherapy Response ◽  
Intrinsic Subtypes ◽  
Mesenchymal Transition

333 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for the molecular classification of breast cancer into subtypes that have clear relevance for prognosis and development of treatment plans. For colorectal cancer (CRC), however, a molecular classification is still missing. Methods: Using gene expression data of 188 stage I-IV colorectal cancer (CRC) patients, a molecular subtype classification was developed. The classifier was validated in 543 stage II and III patients and the subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular marker status and chemotherapy response. Results: CRC is a heterogeneous disease that consists of at least three major intrinsic subtypes (A-, B-, C-type). The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. C-type patients have the worst outcome, a mesenchymal gene expression phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A-type or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype, and benefit from adjuvant chemotherapy. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A-type and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Conclusions: We have developed a diagnostic single sample predictor that allows the classification of CRC tumors of different intrinsic molecular subtypes. These subtypes are potentially clinically relevant, as they differ in their underlying biology and clinical outcome and consequently require different treatment strategies. [Table: see text]

Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3530-3530
Author(s):  
Ramon Salazar ◽  
Paul Roepman ◽  
Josep Tabernero ◽  
Andreas Schlicker ◽  
Ian Majewski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adjuvant Chemotherapy ◽  
Mismatch Repair ◽  
Mutation Frequency ◽  
Epithelial To Mesenchymal Transition ◽  
Chemotherapy Response ◽  
Expression Data ◽  
Intrinsic Subtypes ◽  
Mesenchymal Transition ◽  
Genome Expression

3530 Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for molecular classification of breast cancer into subtypes that have clear relevance for prognosis and treatment. A similar classification is still missing for colorectal cancer (CRC). Methods: Using full genome expression data of 188 stage I-IV CRC patients, an unsupervised clustering revealed three major subtypes (A-, B-, C-type). A molecular subtype classification was developed and validated in 543 stage II and III patients. The subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular markers status and chemotherapy response. In addition, subtypes were determined on 173 samples from The Cancer Genome Atlas (TCGA) colon dataset with Agilent genome expression data. Results: C-type patients have the worst outcome, a mesenchymal phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A- or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype and benefit from adjuvant chemotherapy. A- and C-type groups are enriched for tumors having oncogenic BRAF mutations and a deficient DNA mismatch repair system. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A- and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Finally, CRC subtyping was confirmed in the colon TCGA dataset with 26 samples classified as A-type, 110 as B-type and 37 as C-type. In agreement with the different aggressiveness of the subtypes, A-type tumors were less prevalent in stage IV while C-type were less prevalent in stage I CRC. Conclusions: The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. These subtypes are clinically relevant, as they differ in their underlying biology and might require different treatment strategies.

scholarly journals Molecular Classification and Tumor Microenvironment Characterization of Gallbladder Cancer by Comprehensive Genomic and Transcriptomic Analysis

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 733
Author(s):  
Nobutaka Ebata ◽  
Masashi Fujita ◽  
Shota Sasagawa ◽  
Kazuhiro Maejima ◽  
Yuki Okawa ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Gallbladder Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Classification ◽  
Mesenchymal Transition ◽  
Elevated Expression ◽  
Fresh Frozen ◽  
Therapeutic Decision Making

Gallbladder cancer (GBC), a rare but lethal disease, is often diagnosed at advanced stages. So far, molecular characterization of GBC is insufficient, and a comprehensive molecular portrait is warranted to uncover new targets and classify GBC. We performed a transcriptome analysis of both coding and non-coding RNAs from 36 GBC fresh-frozen samples. The results were integrated with those of comprehensive mutation profiling based on whole-genome or exome sequencing. The clustering analysis of RNA-seq data facilitated the classification of GBCs into two subclasses, characterized by high or low expression levels of TME (tumor microenvironment) genes. A correlation was observed between gene expression and pathological immunostaining. TME-rich tumors showed significantly poor prognosis and higher recurrence rate than TME-poor tumors. TME-rich tumors showed overexpression of genes involved in epithelial-to-mesenchymal transition (EMT) and inflammation or immune suppression, which was validated by immunostaining. One non-coding RNA, miR125B1, exhibited elevated expression in stroma-rich tumors, and miR125B1 knockout in GBC cell lines decreased its invasion ability and altered the EMT pathway. Mutation profiles revealed TP53 (47%) as the most commonly mutated gene, followed by ELF3 (13%) and ARID1A (11%). Mutations of ARID1A, ERBB3, and the genes related to the TGF-β signaling pathway were enriched in TME-rich tumors. This comprehensive analysis demonstrated that TME, EMT, and TGF-β pathway alterations are the main drivers of GBC and provides a new classification of GBCs that may be useful for therapeutic decision-making.

scholarly journals Polysome Profiling of a Human Glioblastoma Reveals Intratumoral Heterogeneity

2019 ◽  
Vol 20 (9) ◽  
pp. 2177 ◽  
Author(s):  
Fernanda Cristina Sulla Lupinacci ◽  
Hellen Kuasne ◽  
Martin Roffé ◽  
Julia Avian Vassalakis ◽  
Fernanda Ferreira da Silva ◽  
...  
Keyword(s):  
Translational Control ◽  
Tumor Heterogeneity ◽  
Epithelial To Mesenchymal Transition ◽  
Molecular Classification ◽  
High Grade ◽  
Translation Rate ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Polysome Profiling

Glioblastoma (GBM) is one of the most aggressive cancers, with median survival of less than 2 years. Despite of considerable advance in molecular classification of GBMs, no improvements in therapy have been described. The scenario is further complicated by tumor heterogeneity and the relationship among genetic, transcriptional and functional findings. Classically, gene expression has been evaluated by steady-state mRNA, however, this does not take translational control into consideration, which contributes considerably to the composition of the proteome. In this study, we evaluated the transcriptomic and translatomic signature of a GBM obtained from a single patient focusing in tumor heterogeneity. In a sampling of eight fragments, we investigated the translation rates, mTORC1 and ERK1/2 pathways and identified both total and polysome associated mRNAs. An increased translation rate was observed in fragments with high-grade histological features. High-grade histology was also associated with the expression of genes related to extracellular matrix (ECM) and angiogenesis, in both transcriptomes and translatomes. However, genes associated with epithelial to mesenchymal transition and stress response, were observed only in translatomes from high-grade fragments. Overall, our results demonstrate that isolation of translated mRNA can be used to identify biomarkers and reveal previously unrecognized determinants of heterogeneity in GBMs.

MicroRNA regulation of radiation sensitivity in colorectal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 608-608
Author(s):  
Shushan Rajesh Rana ◽  
Katherine Kelley ◽  
Rebecca Ruhl ◽  
Charles R. Thomas ◽  
Vassiliki Liana Tsikitis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
Colorectal Cancers ◽  
Specific Gene ◽  
Mesenchymal Transition

608 Background: Patients with locally advanced colorectal cancer (T3/T4/Node positive) receive neoadjuvant chemoradiation therapy (CRT) and subsequent surgery. While 10-25% of patients have complete response to CRT, the remaining patients undergo extensive tumor excision that leads to quality of life issues. Response to CRT is an independent predictor of overall survival highlighting the importance of improving CRT response rates. Several tumor intrinsic factors govern responses to CRT including specific gene expression programs. Emerging evidence suggests that microRNAs (miRs) modulate gene expression programs in response to radiation. Moreover, miR-processing machinery is frequently mutated in colorectal cancers (TCGA, 2016 provisional). miRs have been implicated in several pathological processes associated with colorectal cancer progression including cancer stemness and epithelial-to-mesenchymal transition (EMT). In this context, we hypothesized that differential expression of miRs regulates colorectal cancer radiation sensitivity and therefore can be used as a biomarker to predict therapeutic responses to radiation. Methods: To investigate the differences in miR profiles between rectal cancer patients that had either a pathological partial response (PR) or no response (NR), we isolated RNA from FFPE biopsies using the miRvana microRNA isolation kit (Life Technologies). We used the Nanostring miR profiling platform and obtained absolute counts for > 700 human miRs of which ~500 miRs were expressed above detection limits (cut-off of 20 counts after normalization to the top-100 miRs). We performed in vitro gain and loss of studies with miR transfections in human CRC cell lines with RNAimax reagent and used a luminescence-based assay for proliferation (Cell titer glo, Promega). We performed surviving fraction assays by seeding cells on 6 well plate and counting colonies stained with Methylene Blue. Results: We identified seventeen miRs that were differentially expressed. Among the most upregulated in this group, miR-451a, inhibited proliferation and colony formation in 2D and 3D assays in the presence of radiation. Conclusions: Our data suggests miRs may alter cell survival pathways and affect tumor radiosensitivity.

scholarly journals NKX6.1 Represses Tumorigenesis, Metastasis, and Chemoresistance in Colorectal Cancer

2020 ◽  
Vol 21 (14) ◽  
pp. 5106
Author(s):  
Hsin-Hua Chung ◽  
Chun-Te Lee ◽  
Je-Ming Hu ◽  
Yu-Ching Chou ◽  
Ya-Wen Lin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Metastasis Suppressor ◽  
Chemotherapy Response ◽  
Factor Activity ◽  
Mesenchymal Transition ◽  
Tumor Suppressive Function ◽  
Migration Response

Accumulating evidence suggests that NKX6.1 (NK homeobox 1) plays a role in various types of cancer. In our previous studies, we identified NKX6.1 hypermethylation as a promising marker and demonstrated that the NKX6.1 gene functions as a metastasis suppressor through the epigenetic regulation of the epithelial-to-mesenchymal transition (EMT) in cervical cancer. More recently, we have demonstrated that NKX6.1 methylation is related to the chemotherapy response in colorectal cancer (CRC). Nevertheless, the biological function of NKX6.1 in the tumorigenesis of CRC remains unclear. In this study, we showed that NKX6.1 suppresses tumorigenic and metastatic ability both in vitro and in vivo. NKX6.1 represses cell invasion partly through the modulation of EMT. The overexpression of NKX6.1 enhances chemosensitivity in CRC cells. To further explore how NKX6.1 exerts its tumor-suppressive function, we used RNA sequencing technology for comprehensive analysis. The results showed that differentially expressed genes (DEGs) were mainly related to cell migration, response to drug, transcription factor activity, and growth factor activity, suggesting that these DEGs are involved in the function of NKX6.1 suppressing cancer invasion and metastasis. Our results demonstrated that NKX6.1 functions as a tumor suppressor partly by repressing EMT and enhancing chemosensitivity in CRC, making it a potential therapeutic target.

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

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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