The predictive value of p53 and p33(ING1b) in patients with Dukes'C colorectal cancer

Bishop Auckland General Hospital, Bishop Auckland, County Durham, UK.
Colorectal Disease (Impact Factor: 2.35). 06/2008; 10(4):344-51. DOI: 10.1111/j.1463-1318.2007.01317.x
Source: PubMed


Identification of biological markers that may predict response to chemotherapy would allow the individualization of treatment by enabling selection of patients most likely to benefit from chemotherapy. The aims of this study were to determine whether p53 mutation status and p53 and p33(ING1b) protein expression can predict which patients with Dukes' C colorectal cancer following curative surgical resection respond to adjuvant chemotherapy with 5-fluorouracil (5-FU).
Patients with Dukes'C colorectal cancer (n = 41) were studied. DNA was extracted and analysed for p53 mutation using PCR-based direct DNA sequencing. Tumours were analysed for p53 protein expression by immunohistochemistry using DO-7 monoclonal antibody and for p33(ING1b) protein expression using GN1 monoclonal antibody.
There was a significant association between p53 mutation status analysed by gene sequencing and overall and metastasis-free survival (P = 0.03 and 0.004, respectively, log-rank test). By contrast, no significant correlation was found between p53 and p33(ING1b) protein expression and overall or metastasis-free survival.
In patients with Dukes'C colorectal cancer who underwent curative surgical resection of the primary tumour, followed by 5-FU-based adjuvant chemotherapy, p53 mutation status as assessed by gene sequencing is a significant predictor of overall and metastasis-free survival.

6 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacological treatment of colorectal cancer has improved survival rates in recent years. Individual genetic variation in genes associated with metabolism and targets of commonly used drugs can be responsible for variability in treatment outcome and toxicity. Diverse study designs have been used and heterogeneous end points evaluated by studies assessing the association of genetic markers with treatment outcome. We conducted this systematic review, including 51 studies, to present a comprehensive overview and draw further conclusions. To facilitate comparison of reported study results, risk estimates for observed genetic variants in 33 key genes are presented using defined reference categories and recalculated risk estimates based on data provided in original publications, where necessary. Overall, evidence indicates associations of the UGT1A1(*) 28 variant genotype with toxicity after irinotecan treatment, mutations in GSTP1-105 with improved treatment outcome and the XPD-751 variant genotype with poor treatment outcome after oxaliplatin treatment, and amplification of the EGFR gene with improved treatment outcome after therapy with monoclonal antibodies. Adequately powered prospective investigations designed specifically for pharmacogenetics are needed.
    Pharmacogenomics 09/2008; 9(8):1079-99. DOI:10.2217/14622416.9.8.1079 · 3.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The inhibitor of growth (ING) gene family proteins regulate many critical cellular processes such as cell proliferation and growth, apoptosis, DNA repair, senescence, angiogenesis, and drug resistance. Their transcripts and proteins are differentially expressed in health and disease and there is evidence for developmental regulation. The vast majority of studies have characterized ING levels in the context of cancer. However, relatively little attention has been paid to the expression of ING family members in other contexts. This review summarizes the findings from human and animal model systems that provide insight into the factors influencing the expression of these important proteins. We examine the influence of cell cycle and aging as well as genotoxic stress on ING expression levels and evaluate several emerging areas of inquiry demonstrating that ING gene activity may be modulated by factors such as the p53 tumor suppressor, DNA methylation, and ING proteins themselves with external factors such as hormones, reactive oxygen species, TGFbeta signalling, and other proteins of pathological significance also influencing ING levels. We then briefly discuss the influence of post-translational modification and changes in subcellular localization as it pertains to modulation of ING expression. Understanding how ING expression is modulated represents a vital aspect of effective drug targeting strategies.
    Current drug targets 06/2009; 10(5):392-405. DOI:10.2174/138945009788185095 · 3.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Inhibitor of Growth (ING) gene family is an emerging putative type II tumor suppressor gene (TSG). Proteins of INGs (ING1-5), critical modulator of the histone code via PHD fingers, are able to suppress cell growth and proliferation, induce apoptosis, and modulate cell cycle progression. ING proteins are involved in transcriptional regulation of genes, such as the p53-inducible gene p21. ING proteins also serve as shuttling proteins between nucleus and cytoplasm, and dysregulation of this nucleocytoplasmic traffic has been shown in some cancer cells. In cancer cells, ING mRNA levels are often lost or suppressed but the genes are rarely mutated. Recently the potential roles of ING proteins as prognostic biomarkers, detection of aggressive behavior of the tumor as well as prediction of chemo-radiotherapy response have also emerged. In this review, we summarize the up-to-date knowledge on functions of the ING proteins, the protein status in human tumors and discuss as a potential target in the molecular diagnostics and therapy of cancer.
    Current drug targets 06/2009; 10(5):465-76. DOI:10.2174/138945009788185086 · 3.02 Impact Factor
Show more