Pathway-Based Evaluation in Early Onset Colorectal Cancer Suggests Focal Adhesion and Immunosuppression along with Epithelial-Mesenchymal Transition

Colorectal cancer (CRC) has one of the highest incidences among all cancers. The majority of CRCs are sporadic cancers that occur in individuals without family histories of CRC or inherited mutations. Unfortunately, whole-genome expression studies of sporadic CRCs are limited. A recent study used microarray techniques to identify a predictor gene set indicative of susceptibility to early-onset CRC. However, the molecular mechanisms of the predictor gene set were not fully investigated in the previous study. To understand the functional roles of the predictor gene set, in the present study we applied a subpathway-based statistical model to the microarray data from the previous study and identified mechanisms that are reasonably associated with the predictor gene set. Interestingly, significant subpathways belonging to 2 KEGG pathways (focal adhesion; natural killer cell-mediated cytotoxicity) were found to be involved in the early-onset CRC patients. We also showed that the 2 pathways were functionally involved in the predictor gene set using a text-mining technique. Entry of a single member of the predictor gene set triggered a focal adhesion pathway, which confers anti-apoptosis in the early-onset CRC patients. Furthermore, intensive inspection of the predictor gene set in terms of the 2 pathways suggested that some entries of the predictor gene set were implicated in immunosuppression along with epithelial-mesenchymal transition (EMT) in the early-onset CRC patients. In addition, we compared our subpathway-based statistical model with a gene set-based statistical model, MIT Gene Set Enrichment Analysis (GSEA). Our method showed better performance than GSEA in the sense that our method was more consistent with a well-known cancer-related pathway set. Thus, the biological suggestion generated by our subpathway-based approach seems quite reasonable and warrants a further experimental study on early-onset CRC in terms of dedifferentiation or differentiation, which is underscored in EMT and immunosuppression

Hepatocellular carcinoma

Primary hepatocellular carcinoma is one of the 10 most common tumours, and the most common primary liver malignancy, in the world. In the majority of cases, it occurs against a background of hepatitis B or C viral infection and/or liver cirrhosis, and is associated with a dismal prognosis of a few months. Current treatments in routine clinical practice are surgical resection and liver transplantation, but these therapies are applicable to only a small proportion of patients and prolongation of survival is restricted. Other treatment options include intra-arterial chemotherapy, transcatheter arterial chemoembolisation, percutaneous ethanol injection, cryotherapy, thermotherapy, proton therapy, or a wide range of their possible combinations. The current lack of definitive data, however, limits the use of these therapies. Another option is gene therapy, which although in its infancy at the present time, may have a significant role to play in the future management of hepatocellular carcinoma.


Keywords: hepatocellular carcinoma; hepatic resection; liver transplantation; transcatheter arterial chemoembolisatio

A “field change” of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma

BACKGROUND: Colorectal cancer is associated with a “field change” of increased proliferation throughout the colonic and rectal mucosa. Both proliferation and apoptosis are disrupted during carcinogenesis. Whether altered apoptosis contributes to this field change of microscopic abnormality is, however, unclear. Bcl‐xL is an anti‐apoptotic protein that inhibits apoptosis by preventing release of cytochrome c, a recognised pathway to cell death. AIM: To determine whether Bcl‐xL inhibition of apoptosis is increased in colorectal mucosa adjacent to colorectal adenocarcinoma over that in normal non‐neoplastic colorectal mucosa. PATIENTS: Patients undergoing surgical resection for neoplastic (adenocarcinoma) or non‐neoplastic disease of the colorectum (rectal prolapse, diverticular disease or volvulus). METHODS: Formalin‐fixed, paraffin‐wax‐embedded surgical colorectal resection specimens were immunostained for Bcl‐xL protein. Labelling indices were determined by counting the proportion of positively stained cells in mucosal crypts. RESULTS: 85 patients were studied. Bcl‐xL immunostaining was most marked in the upper third of mucosal crypts. It occurred in a minority of samples from non‐neoplastic colorectal mucosa, but was seen in most mucosal samples adjacent to colorectal adenocarcinoma. Significant increases (p<0.001) were observed in Bcl‐xL labelling indices in the mucosa at 1 cm (n = 46, median labelling index 31.8%, interquartile range 8.3–43.9%) and at 10 cm (n = 52, median labelling index 22.0%, interquartile range 0.0–36.3%) from colorectal carcinoma, compared with normal, non‐neoplastic colorectal mucosa (n = 22, median labelling index 0.0%, interquartile range 0.0–0.0%). CONCLUSIONS: The findings are consistent with a field change of inhibited apoptosis in mucosa adjacent to colorectal carcinoma

p16INK4a Gene Promoter Hypermethylation in Mucosa as a Prognostic Factor for Patients with Colorectal Cancer

Low gene expression of folylpolyglutamate synthase (FPGS) in colorectal mucosa correlates with low folate levels and poor survival of colorectal cancer (CRC) patients. Because gene-specific hypermethylation is affected by the folate level, the hypermethylation status in mucosa may also be linked to clinical outcome of CRC patients. The tumor suppressor gene p16INK4a (p16) regulates the cell cycle and angiogenic switch. In human neoplastic tissues, the main mechanism of p16 inactivation is promoter methylation. The aim of the study was to determine whether hypermethylation of the p16 promoter could be detected in mucosa of CRC patients (n = 181) and to analyze if hypermethylation was related to survival. The relation between p16 hypermethylation and expression of FPGS and two other folate-associated genes, reduced folate carrier 1 (RFC-1), and thymidylate synthase (TS), was analyzed (n = 63). The results showed that p16 was hypermethylated in 65 (36%) of the mucosa samples and that hypermethylation was age-related (P = 0.029). After adjustment for known risk factors, Cox regression analysis showed that Dukes’ A-C patients with p16 hypermethylation in mucosa had an increased risk of cancer-related death (hazard ratio = 2.9, P = 0.007) and shorter disease-free survival (hazard ratio = 2.5, P = 0.015) compared with patients with no p16 hypermethylation. RFC-1 and FPGS gene expression levels were significantly correlated in patients lacking p16 hypermethylation in mucosa (P = 0.0003), but not at all correlated in patients having hypermethylation in mucosa (P = 1.0). In conclusion, p16 hypermethylation in mucosa of CRC patients was identified as an independent prognostic parameter for cancer-specific survival as well as an independent predictor of DFS. The results suggest that there might be a connection between folate-associated gene expression and p16 methylation status