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Right-side and left-side colon cancer follow different pathways to relapse.

ABSTRACT: There is growing evidence that cancer of the ascending (right-side) colon is different from cancer of the descending (left-side) colon at the molecular level. Using microarray data from 102 right-side colon carcinomas and 95 left-side colon carcinomas we show that different pathways dominate progression to relapse in right-side and left-side colon cancer. Right-side tumors at a high risk for relapse exhibit elevated expression of cell cycle control genes and elevated Wnt signaling. On the other hand, relapse-prone left-side tumors show elevated expression of genes that promote stromal expansion and reduced expression of tumor suppressor genes that initiate Wnt signaling. Single gene prognostic biomarkers are found separately for right-side and left-side disease. In left-side tumors with low expression levels of NADPH oxidase 4 (NOX4) the 5-yr relapse-free survival probability is 0.89 95% CI (0.80-0.99), and in tumors with elevated NOX4 expression the probability is 0.51 95% CI (0.37-0.70). Right-side tumors with elevated expression levels of caudal type homeobox 2 (CDX2) have a 5-yr relapse-free survival probability of 0.88 95% CI (0.80-0.96), and those with low CDX2 expression have a corresponding probability of 0.39 95% CI (0.15-0.78). Both NOX4 and CDX2 are much less prognostic on the opposite sides. This newly identified role of NOX4 in colon cancer is further investigated using the SW620 lymph node metastasis colon adenocarcinoma cell line and RNA interference. We show that NOX4 is expressed in the SW620 cell line and that application of NOX4 siRNA causes a significant reduction in reactive oxidative species production.

SUBMITTER: Bauer KM

PROVIDER: S-EPMC4104680 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Right-side and left-side colon cancer follow different pathways to relapse.

Bauer Kerry M KM Hummon Amanda B AB Buechler Steven S

Molecular carcinogenesis 20110607 5

There is growing evidence that cancer of the ascending (right-side) colon is different from cancer of the descending (left-side) colon at the molecular level. Using microarray data from 102 right-side colon carcinomas and 95 left-side colon carcinomas we show that different pathways dominate progression to relapse in right-side and left-side colon cancer. Right-side tumors at a high risk for relapse exhibit elevated expression of cell cycle control genes and elevated Wnt signaling. On the other ...[more]

PMID: 21656576

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Project description:BackgroundColon cancer is one of the most common tumors in the digestive tract. Studies of left-side colon cancer (LCC) and right-side colon cancer (RCC) show that these two subtypes have different prognoses, outcomes, and clinical responses to chemotherapy. Therefore, a better understanding of the importance of the clinical classifications of the anatomic subtypes of colon cancer is needed.MethodsWe collected colon cancer patients' transcriptome data, clinical information, and somatic mutation data from the Cancer Genome Atlas (TCGA) database portal. The transcriptome data were taken from 390 colon cancer patients (172 LCC samples and 218 RCC samples); the somatic mutation data included 142 LCC samples and 187 RCC samples. We compared the expression and prognostic differences of LCC and RCC by conducting a multi-omics analysis of each using the clinical characteristics, immune microenvironment, transcriptomic differences, and mutation differences. The prognostic signatures was validated using the internal testing set, complete set, and external testing set (GSE39582). We also verified the independent prognostic value of the signature.ResultsThe results of our clinical characteristic analysis showed that RCC had a significantly worse prognosis than LCC. The analysis of the immune microenvironment showed that immune infiltration was more common in RCC than LCC. The results of differential gene analysis showed that there were 360 differentially expressed genes, with 142 upregulated genes in LCC and 218 upregulated genes in RCC. The mutation frequency of RCC was generally higher than that of LCC. BRAF and KRAS gene mutations were the dominant genes mutations in RCC, and they had a strong mutual exclusion with APC, while APC gene mutation was the dominant gene mutation in LCC. This suggests that the molecular mechanisms of RCC and LCC differed. The 4-mRNA and 6-mRNA in the prognostic signatures of LCC and RCC, respectively, were highly predictive and may be used as independent prognostic factors.ConclusionThe clinical classification of the anatomic subtypes of colon cancer is of great significance for early diagnosis and prognostic risk assessment. Our study provides directions for individualized treatment of left and right colon cancer.

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.

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.

Project description:GoalsWe aim to draw a conclusion which type of hepatectomy could be the priority for hilar cholangiocarcinoma patients.BackgroundSurgery is established as only potentially curative treatment for hilar cholangiocarcinoma. However, whether hepatectomy should be preferred to the left-side hepatectomy, which includes left hemihepatectomy, extended left hemihepatectomy, and left trisectionectomy, or right-side hepatectomy, which represents right hemihepatectomy, extended right hemihepatectomy, and right trisectionectomy, is debated. In this meta-analysis, we evaluated and compared the efficacy and safety of left-side hepatectomy and right-side hepatectomy in patients with hilar cholangiocarcinoma.StudyWe systematically retrieved the MEDLINE, PubMed, and Cochrane library and related bibliography up to February 2020. The primary outcome is overall survival, and the secondary outcome includes 1-, 3-, and 5-year survival rates, morbidity, mortality, R0 resection rate, and operation time. Based on heterogeneity, fixed-effects model or random-effects models were established through meta-analysis.ResultsEleven studies (11 cohort studies, totally 1031 patients) were involved in this study. The overall survival of patients who underwent left-side hepatectomy was comparable to that of patients who underwent right-side hepatectomy (hazard ratio, 1.27 [95% confidence interval, 0.98-1.63]). And there was no significant difference observed in 1-year (relative risk, 1.01 [95% CI, 0.89-1.15]), 3-year (relative risk, 0.94 [95% confidence interval, 0.80-1.11]), and 5-year survival (relative risk, 0.82 [95% confidence interval, 0.67-1.01]) rates between the left-side hepatectomy group and the right-side hepatectomy group. Comparing with the right-side hepatectomy cluster, the hilar cholangiocarcinoma patients in the left-side hepatectomy cluster presented better overall postoperative morbidity (relative risk, 0.82 [95% confidence interval, 0.71-0.96]) and major postoperative morbidity (relative risk, 0.73 [95% confidence interval, 0.56-0.95]). The post-hepatectomy liver failure rate (relative risk, 0.22 [95% confidence interval, 0.09-0.56]) and procedure-related mortality (relative risk, 0.41 [95% confidence interval, 0.23-0.70]) in the left-side hepatectomy group were better than those of the right-side hepatectomy group. Besides, the R0 resection rate was similar between the left-side hepatectomy group and the right-side hepatectomy group (relative risk, 0.95 [95% confidence interval, 0.87-1.03]). And the operation time for the left-side hepatectomy was significantly longer than that for the right-side hepatectomy (mean difference, 38.68 [95% confidence interval, 7.41-69.95]).ConclusionThrough meta-analysis, we explored the comparable long-term outcomes and better short-term outcomes in the left-side hepatectomy group as is compared to the right-side hepatectomy group of hilar cholangiocarcinoma patients. In this study, the evidence obtained might indicate that the choice of left-side hepatectomy or right-side hepatectomy depends on the site of hilar cholangiocarcinoma in every patient.

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Right-side and left-side colon cancer follow different pathways to relapse.

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Right-side and left-side colon cancer follow different pathways to relapse.

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