scholarly journals Gene Expression Profiles Associated with Radio-Responsiveness in Locally Advanced Rectal Cancer

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 500
Author(s):  
Jeeyong Lee ◽  
Junhye Kwon ◽  
DaYeon Kim ◽  
Misun Park ◽  
KwangSeok Kim ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Expression Profiles ◽  
Cell Cycle Control ◽  
Methylation Status ◽  
Locally Advanced ◽  
Gene Expression Profiles ◽  
Advanced Rectal Cancer ◽  
Bioinformatic Analysis ◽  
Locally Advanced Rectal Cancer ◽  
Genes Encoding

LARC patients were sorted according to their radio-responsiveness and patient-derived organoids were established from the respective cancer tissues. Expression profiles for each group were obtained using RNA-seq. Biological and bioinformatic analysis approaches were used in deciphering genes and pathways that participate in the radio-resistance of LARC. Thirty candidate genes encoding proteins involved in radio-responsiveness–related pathways, including the immune system, DNA repair and cell-cycle control, were identified. Interestingly, one of the candidate genes, cathepsin E (CTSE), exhibited differential methylation at the promoter region that was inversely correlated with the radio-resistance of patient-derived organoids, suggesting that methylation status could contribute to radio-responsiveness. On the basis of these results, we plan to pursue development of a gene chip for diagnosing the radio-responsiveness of LARC patients, with the hope that our efforts will ultimately improve the prognosis of LARC patients.

scholarly journals Validation of microRNA-199b as A Promising Predictor of Outcome and Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer Patients

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 5003
Author(s):  
Ion Cristóbal ◽  
Andrea Santos ◽  
Jaime Rubio ◽  
Cristina Caramés ◽  
Sandra Zazo ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Expression Profiles ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Molecular Target ◽  
Positive Lymph Node ◽  
Prognostic Impact ◽  
Colorectal Cancer Cells

The absence of established predictive markers with value to anticipate response to neoadjuvant 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT) represents a current major challenge in locally advanced rectal cancer (LARC). The tumor suppressor microRNA (miR)-199b has been reported to play a key role determining 5-FU sensitivity of colorectal cancer cells through the regulation of several signaling pathways, and has emerged as a novel molecular target to overcome the 5-FU resistant phenotype. Moreover, miR-199b downregulation was described as a common alteration that predicts lack of response to preoperative CRT in LARC but this issue needs to be confirmed in independent larger cohorts. Here, we evaluate the clinical impact of miR-199b in LARC and perform additional analyses to further clarify its potential relevance as novel marker in this disease. Thus, miR-199b expression was quantified by real-time-PCR in a cohort of 185 LARC patients, observing this miR downregulated in 22.2% of cases and significantly associated with higher tumor size (p = 0.026) and positive lymph node after CRT (p = 0.005), and higher pathological stage (p = 0.004). Notably, this alteration showed a strong independent predictive value of poor pathological response to neoadjuvant CRT (p = 0.004). Moreover, the subgroup of cases with low miR-199b levels had a markedly shorter overall (p < 001) and event-free survival (p < 0.001), and multivariate analyses showed that miR-199b deregulation represents an independent prognosticator for patient outcome in LARC. Interestingly, the prognostic impact of this miR was strongly significant in both younger and elderly patients, and was very effective determining patient recurrence (p = 0.004). Finally, we compared miR-199b expression profiles in a set of cases with pre and post-treatment samples available, observing that only a minimal response leads to miR-199b increase levels, further suggesting its potential clinical and therapeutic relevance as a promising marker and novel molecular target for the management of LARC.

scholarly journals Methylation status of p16 and p14 genes in locally advanced rectal cancer: Potential clinical implication

2018 ◽  
Vol 70 (4) ◽  
pp. 681-690
Author(s):  
Bojana Kozik ◽  
Nikola Kokanov ◽  
Slavica Knezevic-Usaj ◽  
Ivan Nikolic ◽  
Radoslav Davidovic ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Methylation Status ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Vegf Expression ◽  
Egfr Expression

Methylation of p16 and p14 genes is a common event in colorectal cancers; however, their exact role in the prediction of patients? outcome is unclear. We conducted this retrospective study to evaluate their potential predictive and/or prognostic roles. Methylation-specific PCR was used to examine the methylation status of p16 and p14 in pretherapeutic and preoperative biopsy specimens of 60 patients with locally advanced rectal cancer. The methylation status of the examined genes did not affect the response to preoperative chemoradiotherapy (CRT), recurrence rate and overall survival. However, patients with a simultaneous presence of either p16 or p14 methylation and high vascular endothelial growth factor (VEGF) expression showed a significantly worse response to CRT (p=0.005 and p=0.038, respectively). Moreover, patients with both p16 methylation and high VEGF expression had significantly shorter overall survival (p=0.010), while no such association was found in patients with p14 methylation and high VEGF expression. On the other hand, a subgroup of patients with p16 methylation and low VEGF and high epidermal growth factor receptor (EGFR) expression showed a significantly better response to CRT (p=0.024). The obtained results point to the importance of p16 and p14 methylation analyses in combination with VEGF and EGFR expression, aimed at better predicting treatment response and patient outcome.

scholarly journals LncRNAs Signature Associated with Chemoradiotherapy Response and Prognosis in Locally Advanced Rectal Cancer

2021 ◽  
Author(s):  
Yiyi Zhang ◽  
Binjie Guan ◽  
Yong Wu ◽  
Fan Du ◽  
Jinfu Zhuang ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cell Lines ◽  
Expression Profiles ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Lncrna Expression ◽  
Cox Analysis

Abstract Background Long non-coding RNAs (lncRNAs) are promising diagnostic and prognostic biomarkers in cancers. Neoadjuvant chemoradiotherapy (NCRT) is the standard of care for patients with locally advanced rectal cancer (LARC). However, studies are limited regarding lncRNAs associated NCRT response and prognosis of LARC patients. This study aimed to identify lncRNAs associated with NCRT response and prognosis in CRC patients, and to explore potential mechanisms. Methods LncRNA expression profiles from our previous gene chip data basing on the LASSO to identify a four-lncRNA signature that predicted NCRT response and prognosis and further validated in 138 colorectal cancer (CRC) patients and 36 LARC patients from our center. A Cox regression model was performed to identify prognostic risk factors. Moreover, we identified the function of the LINC00909 in vivo and in vitro in CRC cell lines. Results Four hub lncRNAs (DBET, LINC00909, FLJ33534, and HSD52) were screened by comparing the relative lncRNA expression of NCRT-responsive and non-responsive patients (AUC = 0.68, 0.73, 0.73, and 0.70, respectively, all p < 0.05). A competing endogenous RNA (ceRNA) network was constructed based on the four lncRNAs. Moreover, the four lncRNAs expression was identified by the external data in cancerous and adjacent non-cancerous tissues in CRC patients. The results demonstrated that the expression of the four lncRNAs was lower in the normal tissues than in the cancerous tissues (all p < 0.05), and the COX analysis demonstrated that the DBET, LINC00909 and FLJ33534 were assocaited with the DFS in CRC patients. The four lncRNAs were also identified in the LARC following NCRT patients, and the result demonstrated that LINC00909 and FLJ33534 had powerful ability to predict the NCRT response and prognosis (all p < 0.05). Basing on the multivariate COX analysis, we constructed a risk score and verified in the CRC and LARC patients in predicting NCRT response and prognosis. Moreover, The expression and prognosis of the DBET, LINC00909 and FLJ33534 in the CRC tissues were identified in the R2 platform and Oncomine database. Moreover, the over-expression LINC00909 cell lines demonstrated that over-expressed the LINC00909 increased the cell lines resistance to the 5-FU and radiotherapy in vivo and in vitro. Conclusion Our findings showed that DBET, LINC00909, and FLJ33534 could serve as novel biomarkers for prediction of NCRT response and prognosis in CRC patients. And LINC00909 could be a novel therapeutic targets in enhancing the NCRT response.

scholarly journals A 41-Gene Pair Signature for Predicting the Pathological Response of Locally Advanced Rectal Cancer to Neoadjuvant Chemoradiation

2021 ◽  
Vol 8 ◽  
Author(s):  
Zhengfa Xue ◽  
Shuxin Yang ◽  
Yun Luo ◽  
Hao Cai ◽  
Ming He ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Gene Pair ◽  
Expression Profiles ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Chemoradiation ◽  
Pathological Response ◽  
Gene Pairs

Background and Purpose: Pathological response status is a standard reference for the early evaluation of the effect of neoadjuvant chemoradiation (nCRT) on locally advanced rectal cancer (LARC) patients. Various patients respond differently to nCRT, but identifying the pathological response of LARC to nCRT remains a challenge. Therefore, we aimed to identify a signature that can predict the response of LARC to nCRT.Material and Methods: The gene expression profiles of 111 LARC patients receiving fluorouracil-based nCRT were used to obtain gene pairs with within-sample relative expression orderings related to pathological response. These reversal gene pairs were ranked according to the mean decrease Gini index provided by the random forest algorithm to obtain the signature. This signature was verified in two public cohorts of 46 and 42 samples, and a cohort of 33 samples measured at our laboratory. In addition, the signature was used to predict disease-free survival benefits in a series of colorectal cancer datasets.Results: A 41-gene pair signature (41-GPS) was identified in the training cohort with an accuracy of 84.68% and an area under the receiver operating characteristic curve (AUC) of 0.94. In the two public test cohorts, the accuracy was 93.37 and 73.81%, with AUCs of 0.97 and 0.86, respectively. In our dataset, the AUC was 0.80. The results of the survival analysis show that 41-GPS plays an effective role in identifying patients who will respond to nCRT and have a better prognosis.Conclusion: The signature consisting of 41 gene pairs can robustly predict the clinical pathological response of LARC patients to nCRT.

Next-generation expression analysis (NanoString) to develop prognostic and predictive gene signatures for patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 700-700
Author(s):  
Annalisa Milano ◽  
Marina Borro ◽  
Emanuela Pilozzi ◽  
Andrea Montori ◽  
Marco Mazzotta ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Regression ◽  
Wide Spectrum ◽  
Expression Profiles ◽  
Geometric Mean ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Tumor Regression Grade

700 Background: The standard of care for locally advanced rectal cancer (RC) is neoadjuvant chemoradiotherapy (CRT) with 5FU aimed to tumor downstaging prior to radical resection but there is a wide spectrum of responses to it, from none to complete. The aim of this project is to validate top candidate genes previously identified by microarray studies as prognostic and predictive classifiers of locally advanced RC, using the NanoString nCounter Platform. Methods: Two cohorts of RC patients were identified according to tumor regression grade (TRG) of AJCC Staging Manual (7th) system: 1) good prognosis: patients that after neoadjuvant CRT obtained TRG0 (complete response); 2) poor prognosis: patients with TRG1 (moderate response), patients with TRG2 (minimum response rate) and patients with TRG3 (poor response). Pre-treatment biopsies tissues from ten TRG0 patients (ID TRG0bio) and thirteen TRG1-3 patients (ID TRG1-3bio) were macro-dissected from FFPE sections, RNA isolated and used for expression profiling of a 305 genes custom code set consisting of 12 normalizer genes, 101 prognostic genes (markers of stemness, invasiveness, proliferation, drug-resistance), 192 predictive genes (involved in response to 5-FU, to radiation therapy and in the response to CRT). All samples were normalized using the geometric mean of the housekeeper genes. P-values were calculated by student’s t-test and was consider significance if was less than 0.05. Gene-specific RNA expression profiles were compared using Spearman's correlation. The heat map was generated using MeV 4.9.0. Results: When we compared TRG0bio to TRG1-3bio tissues, among the 305 genes assayed, changes in expression levels of 18 genes (SSB, GAPDH, TXNDC9, DUT, PKM, STAT1,SLC28A3, DAG1, TYMS, FERMT1, ARNT,SLC6A6, SMAD3, SCRN1, POU5F1, GNG4, PDRG1, ATP5E) were statistically significant. Conclusions: Results suggest that TRG0 RC is characterized by distinct molecular events compared TRG1-3 disease. Next steps will be: to amplify sample size, to understand signaling pathways of top differentially expressed genes and to validate prospectively our gene signature.

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