Multi-omics characterization of left-right colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3542-3542
Author(s):  
John Marshall ◽  
Takayuki Yoshino ◽  
Sun Young Rha ◽  
David N. Church ◽  
Anelisa Kruschewsky Coutinho ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Biology ◽  
Normal Tissue ◽  
Molecular Mechanisms ◽  
Clinical Information ◽  
Molecular Testing ◽  
Primary Tumors ◽  
Ischemia Time ◽  
Normal Tissues

3542 Background: Right (R) vs left (L) sided colorectal cancers are clinically distinguishable based on prognosis and response to certain therapies, but as of yet, limited data have emerged to explain these differences. The science of molecular testing has evolved rapidly. Enabled by improved technologies and computing power, it is now feasible to obtain to systematic multi-omic datasets covering DNA, RNA, proteins, phospho-proteins and metabolomics on large numbers of patients. Multi-omic analysis can further define disease specific subgroups but pre-analytic quality of the tissues (ischemia time) and comparison to normal tissue controls is paramount to optimize results. Methods: Following informed consent, 450 colorectal cancer primary tumors and paired normal tissues were collected following an SOP to minimize ischemia time, and were analyzed using comprehensive genomics, transcriptomics, proteomics, phosphoproteomics, morphology and annual clinical information. Right (C18.0,2,3) and left (C18.6,7) CRC tumors, normal tissue were compared using machine learning tools to unravel the molecular mechanisms that underpin these clinically distinguishable phenotypes as well as correlating with known genomic metrics such MSI and KRAS mutation status. Results: Through leveraging the tumor and paired normal patient samples, systematic differences between left and right tumor samples were observed including specific molecular events associated with these anatomical differences. The detailed results will be presented at the meeting. Conclusions: Progress in precision medicine requires the inclusion of multi-omics which in turn requires changes to our current SOPs of tissue collection. The ability to define molecular distinctions such as between R and L colon cancer will permit the rapid discovery of clinically useful prognostic and predictive markers, dramatically adding to our fundamental understanding to colon cancer biology. Future work will focus on the discovery of novel targets and signatures, creating innovative tools that depict multi-omic results for clinicians.

scholarly journals The expression and Clinical Significance of miRNA-135a and Bach1 in colorectal cancer

2021 ◽  
Author(s):  
Yang zhi Jiang ◽  
Qing Guo Tao ◽  
fei yan Zhu
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Clinical Information ◽  
Control Group ◽  
Tumor Control ◽  
Cancer Tissue ◽  
Expression Levels ◽  
Real Time Quantitative Pcr ◽  
Normal Tissues ◽  
Cancer Tissues

BACKGROUND AIM To explore the correlation between the expression of miRNA-135a and Bach1 in colorectal cancer tissue and the patient's clinical information.  Methods   60 patients with colorectal carcinoma were treated as a control group. Real-time quantitative PCR assays and immunohistochemistry method were performed to detect the expression of miRNA-135a and Bach1 in 60 colorectal carcinomas and adjacent normal tissues, and the clinical and pathological classifications had also been investigated. The SPSS 19.00 software was used. All data represented mean±SD of three independent experiments. P<0.05 was considered statistically significant. Results  miRNA-135a expression levels increased significantly in the colon cancer tissues compared with the non-tumor control tissues(P<0.01). miRNA-135a expression levels were higher in stage III/IV than in stage I/II colon cancer patients. The expression level of Bach1 in colorectal cancer was significantly lower(P<0.01). Bach1 and miRNA-135a were negatively correlated.  Conclusions:  The levels of miRNA-135a and Bach1 were opposite, the over-expression of miRNA-135a might downregulated the expression of Bach1, which might be involved in the pathogenesis of colorectal cancer.

scholarly journals The expression and Clinical Significance of miRNA-135a and Bach1 in colorectal cancer

2019 ◽  
Author(s):  
Jian Wang ◽  
Yuchen Zhang ◽  
Zhiyang Jiang ◽  
Guoqing Tao ◽  
Fei Yan Zhu
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Colorectal Carcinoma ◽  
Clinical Information ◽  
Control Group ◽  
Tumor Control ◽  
Cancer Tissue ◽  
Expression Levels ◽  
Real Time Quantitative Pcr ◽  
Normal Tissues

Abstract BACKGROUND AIM To explore the correlation between the expression of miRNA-135a and Bach1 in colorectal cancer tissue and the patient's clinical information. Methods 60 patients with colorectal carcinoma were treated as a control group. Real-time quantitative PCR assays and immunohistochemistry method were performed to detect the expression of miRNA-135a and bach1 in 50 colorectal carcinoma and adjacent normal tissues, and the clinical and pathological classifications have also been investigated. The SPSS 19.00 software was used. All data represent mean±SD of three independent experiments. P<0.05 was considered statistically significant. Results miRNA-135a expression levels increase significantly in the colon cancer tissues compared with the non-tumor control tissues(P<0.01). miRNA-135a expression levels are higher in stage III/IV than in stage I/II colon cancer patients. The expression level of Bach1 in colorectal cancer was significantly lower(P<0.01). Bach1 and mirna-135a are negatively correlated. Conclusions: mirna-135a and bach1 showed a negative correlation, it may be one of the important indices for colorectal cancer screening.

scholarly journals The expression and Clinical Significance of miRNA-135a and Bach1 in colorectal cancer

2020 ◽  
Author(s):  
Jian Wang ◽  
Yuchen Zhang ◽  
Zhiyang Jiang ◽  
Guoqing Tao ◽  
fei yan Zhu
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Colorectal Carcinoma ◽  
Clinical Information ◽  
Control Group ◽  
Tumor Control ◽  
Cancer Tissue ◽  
Expression Levels ◽  
Real Time Quantitative Pcr ◽  
Normal Tissues

Abstract AIM To explore the correlation between the expression of miRNA-135a and Bach1 in colorectal cancer tissue and the patient's clinical information. Methods 60 patients with colorectal carcinoma were treated as a control group. Real-time quantitative PCR assays and immunohistochemistry method were performed to detect the expression of miRNA-135a and Bach1 in 60 colorectal carcinoma and adjacent normal tissues, and the clinical and pathological classifications had also been investigated. The SPSS 19.00 software was used. All data represent mean±SD of three independent experiments. P<0.05 was considered statistically significant. Results miRNA-135a expression levels increased significantly in the colon cancer tissues compared with the non-tumor control tissues(P<0.01). miRNA-135a expression levels were higher in stage III/IV than in stage I/II colon cancer patients. The expression level of Bach1 in colorectal cancer was significantly lower(P<0.01). Bach1 and miRNA-135a were negatively correlated. Conclusions: The levels of miRNA-135a and Bach1 were opposite , the over-expression of miRNA-135a might decrease Bach1, which may be involved in the pathogenesis of colorectal cancer.

scholarly journals Hypermethylation of APC2 Is a Predictive Epigenetic Biomarker for Chinese Colorectal Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Yuan He ◽  
Li-Yue Sun ◽  
Jing Wang ◽  
Rui Gong ◽  
Qiong Shao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Sequencing Analysis ◽  
Primary Tumors ◽  
Protein Levels ◽  
Normal Tissues ◽  
Ffpe Tissues ◽  
Epigenetic Biomarker

Objective. To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). Methods. The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n=66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n=44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2′-deoxycytidine (5-AZC). Results. Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p<0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p<0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p<0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59–25.64, p<0.05). Conclusion. This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.

scholarly journals Molecular subtype-specific responses of colon cancer cells to the SMAC mimetic Birinapant

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Michael Fichtner ◽  
Emir Bozkurt ◽  
Manuela Salvucci ◽  
Christopher McCann ◽  
Katherine A. McAllister ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Caspase 8 ◽  
Colon Cancer Cells ◽  
Apoptosis Pathway ◽  
Iap Antagonist

AbstractColorectal cancer is a molecularly heterogeneous disease. Responses to genotoxic chemotherapy in the adjuvant or palliative setting vary greatly between patients, and colorectal cancer cells often resist chemotherapy by evading apoptosis. Antagonists of an inhibitor of apoptosis proteins (IAPs) can restore defective apoptosis signaling by degrading cIAP1 and cIAP2 proteins and by inhibition of XIAP. Due to the multiple molecular mechanisms-of-action of these targets, responses to IAP antagonist may differ between molecularly distinct colon cancer cells. In this study, responses to the IAP antagonist Birinapant and oxaliplatin/5-fluorouracil (5-FU) were investigated in 14 colon cancer cell lines, representing the consensus molecular subtypes (CMS). Treatment with Birinapant alone did not result in a substantial increase in apoptotic cells in this cell line panel. Annexin-V/PI assays quantified by flow cytometry and high-content screening showed that Birinapant increased responses of CMS1 and partially CMS3 cell lines to oxaliplatin/5-FU, whereas CMS2 cells were not effectively sensitized. FRET-based imaging of caspase-8 and -3 activation validated these differences at the single-cell level, with CMS1 cells displaying sustained activation of caspase-8-like activity during Birinapant and oxaliplatin/5-FU co-treatment, ultimately activating the intrinsic mitochondrial apoptosis pathway. In CMS2 cell lines, Birinapant exhibited synergistic effects in combination with TNFα, suggesting that Birinapant can restore extrinsic apoptosis signaling in the context of inflammatory signals in this subtype. To explore this further, we co-cultured CMS2 and CMS1 colon cancer cells with peripheral blood mononuclear cells. We observed increased cell death during Birinapant single treatment in these co-cultures, which was abrogated by anti-TNFα-neutralizing antibodies. Collectively, our study demonstrates that IAP inhibition is a promising modulator of response to oxaliplatin/5-FU in colorectal cancers of the CMS1 subtype, and may show promise as in the CMS2 subtype, suggesting that molecular subtyping may aid as a patient stratification tool for IAP antagonists in this disease.

scholarly journals miR-224 targets BTRC and promotes cell migration and invasion in colorectal cancer

3 Biotech ◽  
2020 ◽  
Vol 10 (11) ◽  
Author(s):  
Qi Zheng ◽  
Jane J. Yu ◽  
Chenggang Li ◽  
Jiali Li ◽  
Jiping Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Migration ◽  
Protein Expression ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Luciferase Assay ◽  
Migration And Invasion ◽  
Cell Migration And Invasion ◽  
Normal Tissues ◽  
The Impact

AbstractOur study aims to investigate the impact of miR-224 on cell migration and invasion in colorectal cancer (CRC) as well as its molecular mechanisms. The results showed that miR-224 was significantly upregulated in CRC compared to normal tissues via the TCGA database. Overexpression of miR-224 promoted CRC cell migration and invasion, while inhibition of miR-224 demonstrated the opposite result via transwell assays. In addition, we found that BTRC was a target gene of miR-224 through the miRecords database and dual-luciferase assay, while western blot together with RT-qPCR showed that inhibition of miR-224 led to elevated BTRC expression in protein level but not in mRNA level, and also decreased the expression of β-catenin. In reference to the Human Protein Atlas, BTRC protein expression was higher in normal tissues than in CRC tissues. In conclusion, miR-224 regulates its target BTRC protein expression and its related Wnt/β-catenin pathway. Its impact on cell migration and invasion in CRC cells suggested that miR-224 could be a prospective therapeutic target for early-stage non-metastatic CRC.

scholarly journals Identifying metastasis-initiating miRNA-target regulations of colorectal cancer from expressional changes in primary tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jongmin Lee ◽  
Hye Kyung Hong ◽  
Sheng-Bin Peng ◽  
Tae Won Kim ◽  
Woo Yong Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastasis ◽  
Cancer Progression ◽  
Cancer Biology ◽  
Mirna Target ◽  
Target Genes ◽  
Expression Profiles ◽  
Statistical Significance ◽  
Primary Tumors ◽  
Significant Difference

Abstract Colorectal cancer (CRC) is prevalent with high mortality, with liver metastasis contributing as a major factor that worsens the survival of patients. The roles of miRNAs in CRC have been elucidated, subsequent to recent studies that suggest the involvement of miRNAs in cancer biology. In this study, we compare the miRNA and gene expression profiles of primary tumors between two groups of patients (with and without liver metastasis) to identify the metastasis-initiating microRNA-target gene regulations. Analysis from 33 patients with metastasis and 14 patients without metastasis revealed that 17 miRNAs and their 198 predicted target genes are differentially expressed, where the target genes showed association with cancer progression and metastasis with statistical significance. In order to evaluate the clinical implications of the findings, we classified CRC patients of independent data into two groups based on the identified miRNA-target regulations, where one group was closer to primary tumors with metastasis than the other group. The comparison of survival showed statistically significant difference, thereby implying the roles of the identified miRNA-target regulations in cancer progression and metastasis. The identification of metastasis-initiating miRNA-target regulations in this study will lead to better understanding of the roles of miRNAs in CRC progression.

scholarly journals A network view of microRNA and gene interactions in different pathological stages of colon cancer

2019 ◽  
Vol 12 (S7) ◽  
Author(s):  
Jia Wen ◽  
Benika Hall ◽  
Xinghua Shi
Keyword(s):  
Gene Expression ◽  
Colon Cancer ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Clinical Information ◽  
The Cancer Genome Atlas ◽  
Gene Interactions ◽  
New Strategy ◽  
Pathological Stages

Abstract Background Colon cancer is one of the common cancers in human. Although the number of annual cases has decreased drastically, prognostic screening and translational methods can be improved. Hence, it is critical to understand the molecular mechanisms of disease progression and prognosis. Results In this study, we develop a new strategy for integrating microRNA and gene expression profiles together with clinical information toward understanding the regulation of colon cancer. Particularly, we use this approach to identify microRNA and gene expression networks that are specific to certain pathological stages. To demonstrate the application of our method, we apply this approach to identify microRNA and gene interactions that are specific to pathological stages of colon cancer in The Cancer Genome Atlas (TCGA) datasets. Conclusions Our results show that there are significant differences in network connections between miRNAs and genes in different pathological stages of colon cancer. These findings point to a hypothesis that these networks signify different roles of microRNA and gene regulation in the pathogenesis and tumorigenesis of colon cancer.

Deleted in Colon Cancer Protein Expression in Colorectal Cancer Metastases: A Major Predictor of Survival in Patients With Unresectable Metastatic Disease Receiving Palliative Fluorouracil-Based Chemotherapy

2004 ◽  
Vol 22 (18) ◽  
pp. 3758-3765 ◽  
Author(s):  
Carlo Aschele ◽  
Domizia Debernardis ◽  
Sara Lonardi ◽  
Roberto Bandelloni ◽  
Stefania Casazza ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Regional Lymph Node ◽  
Survival Rates ◽  
Distant Metastases ◽  
Patient Characteristics ◽  
Rank Test ◽  
Primary Tumors ◽  
Major Predictor

Purpose To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. Patients and Methods DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin–modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. Results Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P = .04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. Conclusion Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

scholarly journals Identification of novel alternative splicing isoform biomarkers and their association with overall survival in colorectal cancer

2019 ◽  
Author(s):  
Hongtao Jia ◽  
Aili Wang ◽  
Haifeng Lian ◽  
Yuanyuan Shen ◽  
Qian Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Alternative Splicing ◽  
Cancer Biology ◽  
The Cancer Genome Atlas ◽  
Normal Tissues ◽  
Eukaryotic Gene ◽  
Cancer Genome Atlas ◽  
Alternative Splicing Events ◽  
Therapeutic Tools

Abstract Alternative splicing is an important mechanism of regulating eukaryotic gene expression. Understanding the most common alternative splicing events in colorectal cancer (CRC) will help developing diagnostic, prognostic or therapeutic tools in CRC. Publicly available RNA-seq data of 31 pairs of CRC and normal tissues and 18 pairs of metastatic and normal tissues were used to identify alternative splicing events using PSI and DEXSeq methods. The highly significant splicing events were used to search a database of The Cancer Genome Atlas (TCGA). We identified alternative splicing events in 10 genes marking the signature of CRC (more inclusion of CLK1-E4, COL6A3-E6, CD44v8-10, alternative first exon regulation of ARHGEF9, CHEK1, HKDC1 and HNF4A) or metastasis (decrease of SERPINA1-E1a, CALD-E5b, E6 and FBLN2-E9). Except for CHEK1, all other 9 splicing events were confirmed by TCGA data with 382 CRC tumors and 52 normal controls. Two splicing events (COL6A3 and HKDC1) were found to be significantly associated with patient overall survival. The alternative splicing signatures of the 10 genes are highly consistent with previous reports and/or relevant to cancer biology. The significant association of higher expression of the COL6A3 E5-E6 junction and HKDC1 E1-E2 with better overall survival was firstly reported. This study might be of significant value in the future biomarker, prognosis marker and therapeutics development of CRC.

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