Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in ...colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways - the TGFβ/SMAD and Wnt/β-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.
The characterisation of desmoplastic reaction (DR) has emerged as a new, independent prognostic determinant in colorectal cancer. Herein, we report the validation of its prognostic value in a ...randomised controlled study (SACURA trial).
The study included 991 stage II colon cancer patients. DR was classified by the central review as Mature, Intermediate or Immature based on the presence of hyalinised collagen bundles and myxoid stroma at the desmoplastic front. All clinical and pathological data, including DR characterisations, were prospectively recorded and analysed 5 years after the completion of the registration.
The five-year relapse-free survival (RFS) rate was the highest in the Mature group (N = 638), followed by the Intermediate (N = 294) and Immature groups (N = 59). Multivariate analysis revealed that DR classification was an independent prognostic factor, and based on Harrell's C-index, the Cox model for predicting RFS was significantly improved by including DR. In the conditional inference tree analysis, DR categorisation was the first split factor for predicting RFS, followed by T-stage, microsatellite instability status and budding.
Histological categorisation of DR provides important prognostic information that could contribute to the efficient selection of stage II colon cancer patients who would benefit from postoperative adjuvant therapy.
This study aimed to identify a novel biomarker or a target of treatment for colorectal cancer (CRC).
The expression profiles of cancer cells in 104 patients with CRC were examined using laser ...microdissection and oligonucleotide microarray analysis. Overexpression in CRC cells, especially in patients with distant metastases, was a prerequisite to select candidate genes. The mRNA expression of candidate genes was investigated by quantitative reverse transcriptase PCR (RT-PCR) in 77 patients as a validation study. We analyzed the protein expression and localization of the candidate gene by immunohistochemical study and investigated the relationship between protein expression and clinicopathologic features in 274 CRC patients.
Using microarray analysis, we identified 6 candidate genes related to distant metastases in CRC patients. Among these genes, osteoprotegerin (OPG) is known to be associated with aggressiveness in several cancers through inhibition of apoptosis via neutralization of the function of TNF-related apoptosis-inducing ligand. The mRNA expression of OPG in cancer tissues was significantly higher in patients with distant metastases than those without metastases. Overexpression of OPG protein was associated with significantly worse overall survival and relapse-free survival. Moreover, overexpression of the OPG protein was an independent risk factor for CRC recurrence.
Overexpression of OPG may be a predictive biomarker of CRC recurrence and a target for treatment of this disease.
Purpose
Sarcopenia is reported to be associated with complications after surgery. However, there is no established optimal parameter to determine sarcopenia affecting surgical outcome. This study ...investigated whether morphologic change of the psoas muscle (MPM) reflects sarcopenia and could be a predictor of complications after colorectal cancer surgery.
Methods
Colorectal cancer patients who underwent primary tumor resection with anastomosis between 2015 and 2016 were analyzed. MPM score was evaluated as the ratio of the short-to-long axis of the psoas muscle in CT images at the L3 vertebrae and classified into five MPM grades. Then, the impact of MPM grade on development of postoperative complications was investigated.
Results
A total of 133 patients were studied. MPM score was significantly correlated to the sectional areas of the psoas muscle at the L3 vertebrae which was evaluated by manual tracing. 21.1% of the subjects were classified into severe MPM (defined as MPM grade 3–4). Overall and infectious complications were noted in 37 (27.8%) and 16 (12.0%) patients. Severe MPM (odds ratio OR 2.71, 95% confidence interval CI 1.09–6.73), longer operative time (OR 1.01, 95%CI 1.001–1.01), and open surgery (OR 2.73, 95%CI 1.17–6.35) were identified as independent risk factors of overall complications. Severe MPM (OR 4.26,95%CI 1.38–13.10) and open surgery (OR 3.42, 95%CI 1.11–10.48) were identified as independent factors associated with infectious complications.
Conclusions
MPM grade may be used as a simple and convenient marker of sarcopenia and to identify patients at increased risk of complications after colorectal cancer surgery.
Background
The clinical utility of plasma cell-free DNA in precision cancer medicine has not been established. A pilot study was conducted to investigate the clinical utility of comprehensive genomic ...profiling by liquid biopsy in a Japanese population.
Methods
In this PROFILE study, 102 patients with advanced solid tumors who showed progression with standard systemic therapy underwent liquid biopsy between August 2017 and February 2020. Liquid biopsy was performed using Guardant360.
Results
Of the 102 patients, 56 were women, and the median age was 65 years. Regarding the types of cancer, 31 were hepatobiliary and pancreatic cancer, 17 were gastrointestinal cancer, and 13 were breast cancer. Frequently altered genes were
TP53
(53.9%, 46/102),
KRAS
(25.5%, 26/102),
PIK3CA
(19.6%, 20/102), and
EGFR
(17.6%, 18/102). At least one genetic aberration was detected in 92 patients (90.2%). Actionable mutation was discovered in 88 patients (86.3%), and 67 patients (65.7%) were clinical trial candidates. Of the 102 patients, 22 (21.6%) were able to receive biomarker-matched therapy. Their best responses were as follows: 1 complete response, 3 partial responses, 7 stable diseases, and 11 progressive diseases. Additionally, the treated patients were divided on the basis of matching scores (≥ 50% vs. < 50%). The patients were divided into high and low groups. The high group had a higher disease control rate (DCR) of 75% compared with 20% in the low group (
P
= 0.010).
Conclusions
The results indicate that liquid biopsy is useful for identifying actionable mutations associated with the clinical response of selected patients.
The current histopathological risk-stratification criteria in colorectal cancer (CRC) patients following a curative surgery remain inadequate. In this study, we undertook a systematic, genomewide, ...biomarker discovery approach to identify and validate key EMT-associated genes that may facilitate recurrence prediction in CRC. Genomewide RNA expression profiling results from two datasets (GSE17538; N = 173 and GSE41258; N = 307) were used for biomarker discovery. These results were independently validated in two, large, clinical cohorts (testing cohort; N = 201 and validation cohort; N = 468). We performed Gene Set Enrichment Analysis (GSEA) for understanding the function of the candidate markers, and evaluated their correlation with the mesenchymal CMS4 subtype. We identified integrin subunit beta like 1 (ITGBL1) as a promising candidate biomarker, and its high expression associated with poor overall survival (OS) in stage I-IV patients and relapse-free survival (RFS) in stage I-III patients. Subgroup validation in multiple independent patient cohorts confirmed these findings, and demonstrated that high ITGBL1 expression correlated with shorter RFS in stage II patients. We developed a RFS prediction model which robustly predicted RFS (the area under the receiver operating curve (AUROC): 0.74; hazard ratio (HR): 2.72) in CRC patients. ITGBL1 is a promising EMT-associated biomarker for recurrence prediction in CRC patients, which may contribute to improved risk-stratification in CRC.
Background
Diagnosis of low-grade dysplasia (LGD) is important in the management of ulcerative colitis (UC), but it is often difficult to distinguish LGD from inflammatory regenerative epithelium. ...The unfolded protein response (UPR) is activated in inflammatory bowel disease and malignancies. We aimed to identify a UPR-related gene that is involved in the development of non-UC and UC-associated colorectal cancer (CRC), and to investigate whether the target gene is useful for the diagnosis of LGD.
Methods
Using our microarray gene expression database of 152 CRCs, we identified activating transcription factor 6 (ATF6) as a target gene. Immunohistochemistry (IHC) of ATF6 were analyzed in 137 surgically resected CRCs, 95 endoscopically resected adenomas and pTis cancers, and 136 samples from 51 UC patients (93 colitis without neoplasia, 31 dysplasia, and 12 UC-associated CRC). The diagnostic accuracy of ATF6 and p53 as markers of LGD was assessed.
Results
ATF6 expression was detectable in all CRCs but not in normal colonic mucosa, was elevated with increase in cellular atypia (adenoma with moderate atypia < severe atypia < pTis CRC,
p
< 0.001), and higher in dysplasia and CRC than in non-neoplastic colitis (
p
< 0.001). Notably, the difference between colitis and LGD was significant. Compared to p53-IHC, ATF6-IHC had better diagnostic accuracy for distinguishing LGD from background inflammatory mucosa (sensitivity 70.8 vs. 16.7%, specificity 78.5 vs.71.0%, respectively).
Conclusions
ATF6 was expressed in lesions undergoing pre-cancerous atypical change in both non-UC and UC-associated CRC and may be used to distinguish LGD from inflammatory regenerative epithelium in UC patients.
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