Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Divergent findings regarding the prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) patients exist in current literature. We aim to review data from published studies in order to examine the association between CIMP and CRC prognosis. MATERIALS AND METHODS: A comprehensive search for studies reporting disease-free survival (DFS), overall survival (OS), or cancer-specific mortality of CRC patients stratified by CIMP is carried out. Study findings are summarized descriptively and quantitatively, using adjusted hazard ratios (HRs) as summary statistics. RESULTS: Thirty-three studies reporting survival in 10 635 patients are included for review. Nineteen studies provide data suitable for meta-analysis. The definition of CIMP regarding gene panel, marker threshold, and laboratory method varies across studies. Pooled analysis shows that CIMP is significantly associated with shorter DFS (pooled HR estimate 1.45; 95% confidence interval (CI) 1.07-1.97, Q = 3.95, I(2) = 0%) and OS (pooled HR estimate 1.43; 95% CI 1.18-1.73, Q = 4.03, I(2) = 0%) among CRC patients irrespective of microsatellite instability (MSI) status. Subgroup analysis of microsatellite stable (MSS) CRC patients also shows significant association between shorter OS (pooled HR estimate 1.37; 95% CI 1.12-1.68, Q = 4.45, I(2) = 33%) and CIMP. Seven studies have explored CIMP's value as a predictive factor on stage II and III CRC patient's DFS after receiving adjuvant 5-fluorouracil (5-FU) therapy: of these, four studies showed that adjuvant chemotherapy conferred a DFS benefit among CIMP(+) patients, one concluded to the contrary, and two found no significant correlation. Insufficient data was present for statistical synthesis of CIMP's predictive value among CRC patients receiving adjuvant 5-FU therapy. CONCLUSION: CIMP is independently associated with significantly worse prognosis in CRC patients. However, CIMP's value as a predictive factor in assessing whether adjuvant 5-FU therapy will confer additional survival benefit to CRC patients remained to be determined through future prospective randomized studies.

Role of nuclear architecture in epigenetic alterations in cancer.

It is widely accepted that cancer results from an array of epigenetic and genetic alterations, particularly aberrant epigenetic patterns that are a hallmark of every cancer type studied. Another well-known feature of cancer cells is the array of abnormalities in their nuclear structure. Although it is known that nuclear structure has an important role in the regulation of gene expression, we know little about the direct relationship between nuclear structural alterations and aberrant epigenetic patterns in cancer. Here, we discuss some of the recent studies from our lab and others to understand the relationship between alterations of nuclear architecture and aberrant epigenetic patterns in cancer cells. Although the precise relationship remains elusive, we suggest that changes in nuclear structure and composition could alter long-range genomic interactions and cause global epigenetic changes during tumorigenesis. We emphasize the need for further studies to elucidate the direct relationship between nuclear structure alterations and aberrant epigenetic patterns in cancers.

Direct protein transfer to terminally differentiated muscle cells.

Recently, a new approach for direct protein transfer to mammalian cells based on the herpes simplex virus type 1 protein VP22 has been described. This protein has the remarkable property of intercellular trafficking, which is independent of direct cell contacts and is also retained when fused to heterologous proteins. However, the spreading has only been described for proliferating cells and has also been controversially discussed. In this study we describe the generation of a GFP-VP22 fusion protein which is able to spread in COS-7 cells after transient transfection. Moreover, we show in coculture experiments with transfected COS-7 cells and C2C12 myotubes that this fusion protein is also able to spread into terminally differentiated skeletal muscle cells. These results suggest that VP22 might be a novel therapeutic tool for direct protein transfer not only in proliferating but also in terminally differentiated cells.