Genomic Analysis Reveals Heterogeneity Between Lesions in Synchronous Primary Right-Sided and Left-Sided Colon Cancer.
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ABSTRACT:
SUBMITTER: Hu H
PROVIDER: S-EPMC8371635 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.
| S-EPMC6303985 | biostudies-literature
Project description:Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials. Clearly, the differences in molecular biology among right-sided colon, left-sided colon, and rectal cancers should be further studied in order to account for disparities in clinical outcomes. We profiled 10,570 colorectal tumors (of which 2,413 were identified as arising from the left colon, right colon, or rectum) using next-generation sequencing, immunohistochemistry, chromogenic in-situ hybridization, and fragment analysis (Caris Life Sciences, Phoenix, AZ). Right-sided colon cancers had higher rates of microsatellite instability, more frequent aberrant activation of the EGFR pathway including higher BRAF and PIK3CA mutation rates, and increased mutational burden compared to left-sided colon and rectal cancers. Rectal cancers had higher rates of TOPO1 expression and Her2/neu amplification compared to both left- and right-sided colon cancers. Molecular variations among right-sided colon, left-sided colon, and rectal tumors may contribute to differences in clinical behavior. The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials.
| S-EPMC5689690 | biostudies-other
Project description:Introduction:More and more findings have demonstrated that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) are distinct clinical and biological entities and suggest that they should be treated as different diseases. However, the reasons why RCC and LCC harbor different clinical and biological features remain unclear. Materials and methods:To identify the genomic expression differences between RCC and LCC and uncover the mechanisms underlying these differences, we chose the gene expression profiles of GSE14333 from the Gene Expression Omnibus (GEO) database as an object of study. Then, a systematic and integrative bioinformatics analysis was performed to research the possible mechanism of the differentially expressed (DE) genes from the Gene Expression Omnibus dataset including gene ontology (GO) analysis, pathway enrichment analysis, protein-protein interaction (PPI) network construction, and module analysis. Totally, we extracted 3,793 DE genes from samples of colon cancer including 1,961 genes upregulated in RCC and 1,832 genes upregulated in LCC from the selected dataset. Results:The results of GO and pathway enrichment analysis indicated that RCC and LCC could predispose to different pathways regulated by different genes. Based on the PPI network, PCNA, TP53, HSP90AA1, CSNK2A1, UBB, LRRK2, ABL1, PRKACA, CAV1, and JUN were identified as the key hub genes. Also, significant modules were screened from the PPI network. Conclusion:In conclusion, the present study indicated that the identified genes and pathways may promote new insights into the underlying molecular mechanisms contributing to the difference between RCC and LCC and might be used as specific therapeutic targets and prognostic markers for the personalized treatment of RCC and LCC.
| S-EPMC5797455 | biostudies-literature
Project description:The difference between left- and right-sided colon cancer has become the focus of global attention, and researchers have found differences in the morbidity, molecular biological characteristics, and response to targeted drug therapy between left- and right-sided colon cancer. Therefore, the identification of more effective predictive indicators is critical for providing guidance to future clinical work. We collected samples from different colon sites and regions and analyzed the identities and distributions of differentially expressed species in the microbiota in the left and right sides of the colon to better explore the pathogenesis of colon cancer and provided a basis for individualized drug therapy. We collected samples from different regions in the body of 40 patients with colon cancer, including stool and tissues. The Subjects were classified into four groups, and this classification was mainly based on the colon cancer distribution. The microbiota composition of the left-sided and right-sided colon samples was assessed by specifically amplifying the V3-V4 region of the 16S rDNA gene from DNA extracts from the samples. These amplicons were examined by Illumina HiSeq 2500 sequencing. The microbial taxa in the left-sided colon samples are more abundant than those in the right-sided colon samples. The flora in the left-sided colon samples, such as Clostridium perfringens and Fusobacterium nucleatum, might be associated with VEGF expression and are more likely to promote colon cancer. The microbiota distribution in the right-sided colon samples is less invasive and harmful and particularly rich in Bifidobacterium dentium. In addition, Streptococcus, which is the target of EGFR, was found to be expressed in both the left- and right-sided colon samples but was found at a higher level in the left-sided colon samples. Additionally, the differential pathways involved in the left-sided colon samples mainly mediate DNA damage, methylation, and histone modifications, whereas those in the right-sided colon samples are dominated by DNA synthesis. The comparison of only the geographical differences revealed a significant difference in the distribution of the microbial population. The adherent microbiota composition and structural changes between the left- and right-sided colon samples might contribute to the development of colon cancer, lead to different morbidities, and further affect the prognosis of patients and their sensitivity to targeted drugs. Therefore, the identification of the differential flora in the colon could be used as an indicator for predicting the occurrence and development of colon cancer, which is also beneficial for future individualized drug therapy.
| S-EPMC7726112 | biostudies-literature
Project description:In our study, we obtained paired normal left-sided and right-sided colon mucosa tissues by colonoscopy, and 9,642 individual cells were analyzed by single-cell RNA-seq, which aims to explore the differennces of cell component between the left and the right colon.
2024-06-10 | GSE176499 | GEO
Project description:BackgroundThe distinction between right-sided and left-sided colon adenocarcinoma has recently received considerable. This study aims to identify key MicroRNA (miRNA) and mRNAs in right-sided colon adenocarcinoma (RSCOAD) and left-sided colon adenocarcinoma (LSCOAD) by TCGA integration analysis.MethodsThe miRNA and mRNA expression profiles of a large group of patients with RSCOAD and LSCOAD were obtained from TCGA. The differentially expressed miRNAs (DEmiRNAs) and mRNAs (DEmRNAs) were identified by TCGA integration analysis. The optimal diagnostic miRNA biomarkers for RSCOAD and LSCOAD were identified by Boruta algorithm. We established classification models to distinguish RSCOAD and LSCOAD. Protein-protein interaction (PPI) network analysis, DEmiRNA-DEmRNA interaction analysis, and functional annotation were performed. The expression of selected DEmiRNAs and DEmRNAs was validated by qRT-PCR.ResultsA total of 2534 DEmRNAs (940 downregulated and 1594 upregulated mRNAs) and 54 DEmiRNAs (22 downregulated and 32 upregulated miRNAs) between RSCOAD and LSCOAD were identified. The feature selection procedure was to obtain 22 optimal diagnostic miRNAs biomarkers in RSCOAD compared to LSCOAD. The AUC of the random forests model was 0.869 and the specificity and sensitivity of this model were 79% and 84.6%, respectively. Three DEmiRNAs (hsa-miR-224-5p, hsa-miR-155-5p, and hsa-miR-31-5p) and five DEmRNAs (CXCR4, SMAD4, KRAS, FITM2, and PLAGL2) were identified key DEmiRNAs and DEmRNAs in RSCOAD compared to LSCOAD. The qRT-PCR results of CXCR4, FITM2, TFAP2A, ULBP2, hsa-miR-224-5p, and hsa-miR-155-5p were consistent with our integrated analysis.ConclusionA total of three DEmiRNAs (hsa-miR-224-5p, hsa-miR-155-5p, and hsa-miR-31-5p) and five DEmRNAs (CXCR4, SMAD4, KRAS, FITM2, and PLAGL2) may be involved in the pathogenesis of RSCOAD and LSCOAD which may make a contribution for understanding mechanisms and developing therapeutic strategies for RSCOAD and LSCOAD.
| S-EPMC6470432 | biostudies-literature
Project description:This study aimed to explore the association of tumor sidedness with the prognosis of patients with colon signet ring cell carcinoma (SRCC). Eligible patients were retrieved from the Surveillance, Epidemiology, and End Results database between 2004 and 2015. Cancer-specific survival (CSS) and overall survival (OS) were compared between patients with left-sided colon SRCC and those with right-sided lesions. A total of 2660 patients were included, among them, 1983 (74.5%) had right-sided colon SRCC. Compared to patients with left-sided colon SRCC, those who had the right-sided colon SRCC showed higher proportion of white race, female, aged ??65 years, receiving total colectomy and ??4 regional lymph node dissection; while had lower proportion of advanced AJCC stage. Besides, right-sided patients exhibited superior 5-year CSS (32.74% vs. 25.89%, P?=?0.001) and OS (27.38% vs. 23.02%, P?=?0.024) rates compared with left-sided ones. Multivariate analysis revealed that tumor sidedness was an independent prognostic factor. To be specific, patients with right-sided colon SRCC showed better CSS (HR: 0.873; 95% CI 0.777-0.981; P?=?0.023) and OS (HR: 0.838; 95% CI 0.753-0.965; P?=?0.002). Moreover, subgroup analysis demonstrated superior CSS and OS for right-sided patients in most subgroups. Tumor sidedness was an independent prognostic indicator for colon SRCC. Besides, patients with right-sided colon SRCC have superior prognosis than those with left-sided lesions.
| S-EPMC7578060 | biostudies-literature
Project description:Molecular heterogeneity determines the differences in the pathological features, prognosis and survival after relapse when comparing left-sided colon cancer (LCC) and right-sided colon cancer (RCC). At present, the discrepancy in the underlying molecular events between the two types of colon cancer has not been thoroughly investigated. The present study aimed to explore novel targets to predict the disease stage and prognosis of LCC and RCC. Expression analysis of guanine nucleotide binding-protein γ subunit 4 (GNG4) was performed using the Gene Expression Profiling Interactive Analysis (GEPIA) and Oncomine databases. Survival and association analyses were performed using GEPIA and the colon adenocarcinoma dataset from The Cancer Genome Atlas database. GNG4-positive cells in a tissue microarray were examined using immunohistochemistry. According to the GNG4 expression data from Caucasian patients included in the TCGA dataset, GNG4 was highly expressed and positively associated with pathological stage and overall survival (OS) rates in colon cancer. GNG4 expression was higher in LCC than in RCC. Patients with LCC with high GNG4 expression exhibited higher pathological stage and lower survival rates, whereas this was not observed in patients with RCC. In addition, the clinical tissues used in the microarray showed that GNG4 expression was increased in Chinese patients with LCC compared with that in patients with RCC. Consistently, GNG4 expression was negatively associated with OS in patients with LCC, but not in patients with RCC. However, no association was observed between GNG4 expression and the disease stage of colon cancer in both patients with LCC and RCC. Overall, the molecular heterogeneity of GNG4 in LCC and RCC suggests that GNG4 may be used as a diagnostic and prognostic biomarker in patients with LCC.
| S-EPMC7584031 | biostudies-literature
Project description:Mountain of studies has showed that right-sided colon cancer (RSCC) and left-sided colon cancer (LSCC) have different clinical presentation and biologic features and should be considered as two distinct disease entities. The survival difference between RSCC and LSCC remains controversial. Using Surveillance, Epidemiology, and End Results (SEER) database, we identified colon adenocarcinoma patients from 2004 to 2013. The 5-year cause-specific survival (CSS) was our primary endpoint. All statistical analyses were performed using the Intercooled Stata 13.0. All statistical tests were two-sided. The study included 95,847 (58.72%) RSCC and 67,385 (41.28%) LSCC patients. RSCC patients were older, more often females, more Caucasian, more unmarried, more advanced T and N stage, larger tumor sizes, and more poorly differentiated tumor, while LSCC patients had more stage IV diseases. Location was an independent prognostic factor in the multivariable analysis. Compared with RSCC patients, the hazard ratio for LSCC was 0.87, 95% CI: 0.85-0.89 P < 0.001. There was no survival difference between RSCC and LSCC in the following situations: older than 68 years old, T3-4, N0, poorly differentiated, and undifferentiated diseases. We firstly reported that RSCC patients had a better prognosis than LSCC in mucinous adenocarcinoma/signet ring cell carcinoma patients. RSCC patients also had a better prognosis than LSCC in stage II disease. There is a need for further subdivisions when analyzing the survival difference between RSCC and LSCC patients. RSCC had lower mortality rate than LSCC in stage II disease and mucinous adenocarcinoma/signet ring cell carcinoma patients.
| S-EPMC5911618 | biostudies-literature
Project description:The colon is derived from the embryological midgut and hindgut separately, with the right colon and left colon having different features with regards to both anatomical and physiological characteristics. Cancers located in the right and left colon are referred to as right colon cancer (RCC) and left colon cancer (LCC), respectively, based on their apparent anatomical positions. Increasing evidence supports the notion that not only are there differences in treatment strategies when dealing with RCC and LCC, but molecular features also vary between them, not to mention the distinguishing clinical manifestations. Disease-free survival after radical surgery of both RCC and LCC are similar. In the treatment of RCC, the benefit gained from adjuvant FOLFIRI chemotherapy is superior, or at least similar, to LCC, but inferior to LCC if FOLFOX regimen is applied. On the other hand, metastatic LCC exhibits longer survival than that of RCC in a palliative chemotherapy setting. For KRAS wild-type cancers, LCC benefits more from cetuximab treatment than RCC. Moreover, advanced LCC shows a higher sensitivity to bevacizumab treatment in comparison with advanced RCC. Significant varieties exist at the molecular level between RCC and LCC, which may serve as the cause of all apparent differences. With respect to carcinogenesis mechanisms, RCC is associated with known gene types, such as MMR, KRAS, BRAF, and miRNA-31, while LCC is associated with CIN, p53, NRAS, miRNA-146a, miRNA-147b, and miRNA-1288. Regarding protein expression, RCC is related to GNAS, NQO1, telomerase activity, P-PDH, and annexin A10, while LCC is related to Topo I, TS, and EGFR. In addition, separated pathways dominate progression to relapse in RCC and LCC. Therefore, RCC and LCC should be regarded as two heterogeneous entities, with this heterogeneity being used to stratify patients in order for them to have the optimal, current, and novel therapeutic strategies in clinical practice. Additional research is needed to uncover further differences between RCC and LCC.
| S-EPMC4458758 | biostudies-literature