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Colorectal cancer (CRC) represents a significant health burden worldwide, comprising approximately 10% of annual cancer cases globally. Hepatic metastases are the most common site of CRC metastasis, and are the leading cause of death in CRC patients. There is strong epidemiologic evidence for an inverse association between vitamin D status and risk of CRC; however, the role of vitamin D in the natural history of liver metastases has not yet been investigated. Several researchers have proposed hallmarks of metastases; crucially, metastases can be blocked by interrupting just one rate-limiting step. Vitamin D status has been implicated in each proposed hallmark of metastasis. The aim of this review is to examine the potential role for vitamin D in reducing the development of hepatic metastases from CRC and outline the candidate mechanisms by which vitamin D may mediate these effects. The results of ongoing randomised intervention trials are eagerly awaited to determine whether addressing vitamin D insufficiency in CRC patients could reduce the occurrence of liver metastases, and the consequent morbidity and mortality.

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BACKGROUND AND PURPOSE: Head and neck cancer is common, and understanding the prognosis is an important part of patient management. In addition to the Tumor, Node, Metastasis staging system, tumor biomarkers are becoming more useful in understanding prognosis and directing treatment. We assessed whether MR imaging texture analysis would correctly classify oropharyngeal squamous cell carcinoma according to p53 status. MATERIALS AND METHODS: A cohort of 16 patients with oropharyngeal squamous cell carcinoma was prospectively evaluated by using standard clinical, histopathologic, and imaging techniques. Tumors were stained for p53 and scored by an anatomic pathologist. Regions of interest on MR imaging were selected by a neuroradiologist and then analyzed by using our 2D fast time-frequency transform tool. The quantified textures were assessed by using the subset-size forward-selection algorithm in the Waikato Environment for Knowledge Analysis. Features found to be significant were used to create a statistical model to predict p53 status. The model was tested by using a Bayesian network classifier with 10-fold stratified cross-validation. RESULTS: Feature selection identified 7 significant texture variables that were used in a predictive model. The resulting model predicted p53 status with 81.3% accuracy (P < .05). Cross-validation showed a moderate level of agreement (κ = 0.625). CONCLUSIONS: This study shows that MR imaging texture analysis correctly predicts p53 status in oropharyngeal squamous cell carcinoma with ∼80% accuracy. As our knowledge of and dependence on tumor biomarkers expand, MR imaging texture analysis warrants further study in oropharyngeal squamous cell carcinoma and other head and neck tumors.

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BACKGROUND: Tumour hypoxia is associated with impaired apoptosis, resistance to therapy and poor prognosis. We previously reported that high stromal expression of the endogenous marker of hypoxia, carbonic anhydrase IX (CAIX), is associated with significantly reduced survival in oral squamous cell carcinoma (OSCC). In addition to hypoxia, CAIX expression is regulated by proliferation-associated signalling. We hypothesised that incorporating Ki67, a proliferation marker, into our existing CAIX-based stratification of OSCC would identify patients with the least favourable prognosis. METHODS: Surgically resected tumours from 60 OSCC patients were analysed for CAIX, Ki67 and BAX expression using fluorescence immunohistochemistry and automated quantitative analysis (AQUA). RESULTS: In patients expressing high stromal CAIX (sCAIX), stratification by tumour Ki67 expression revealed significantly distinct survival outcomes (P=0.005). In our OSCC cohort, below-median Ki67 and top-quartile sCAIX expression (Ki67(lo)sCAIX(hi)) were associated with significantly worse disease-specific survival in univariate (HR 7.2 (2.5-20.4), P=0.001) and multivariate (HR 4.2 (1.4-12.8), P=0.011) analyses. Hypoxia is associated with decreased BAX expression; the Ki67(lo)sCAIX(hi) group was more strongly associated with low BAX expression than high sCAIX alone. CONCLUSION: These data suggest that combined analysis of tumour Ki67 and sCAIX expression may provide a more clinically relevant assessment of tumour hypoxia in OSCC.

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Dietary folate has been consistently associated with reduced risk of colorectal cancer (CRC). One of the known biochemical roles of folate is donation of methyl moieties. DNA hypomethylation is an early and almost ubiquitous occurrence in tumor tissue. Therefore, it was originally suggested that adequate folate intake contributed to reduced risk of CRC by facilitating methyl-mediated silencing of oncogenes. Methylene tetrahydrofolate reductase (MTHFR) metabolizes 5,10-MTHF (important in DNA synthesis) to 5-MTHF (contributes to downstream methylation reactions by regeneration of methionine from homocysteine). A common polymorphism in the MTHFR gene (C677T) results in a thermolabile phenotype associated with increased homocysteine levels and DNA hypomethylation. Consistent with the folate/methylation hypothesis, it was originally proposed that C677T may increase risk of CRC due to hypomethylation of oncogenes. However, most subsequent studies have reported a reduced risk associated with this polymorphism. This is inconsistent with methylation as the mechanism by which folate and MTHFR genotype mediate CRC risk. The hypothesis presented here proposes that localized folate depletion combined with the effect of the C677T polymorphism on enzyme stability, impacts on the DNA synthesis pathway and accounts for the observed variation in risk associated with genotype and folate status.

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Glucose transfer from mother to fetus by placental facilitated diffusion is the dominant mechanism by which the fetus acquires glucose. In small for gestational age pregnancies, fetal glucose concentrations tend to be lower than normal and this persists following delivery. GLUT1 is the major glucose transporter in human placenta but there is no evidence of GLUT1 deficiency as a cause of the lower fetal glucose concentration in small for gestational age pregnancy. The physiological and pathological roles of the other glucose transporters (and there are 14 currently described) are unknown. In recent years, the possibility has been raised that the placenta is itself capable of supplying glucose for fetal needs. This hypothesis derived from glucose isotope studies in normal pregnancy, where dilution of glucose isotope was demonstrated in blood samples taken from the fetal circulation during intravenous infusion of glucose isotope in the mother. Although other gluconeogenic enzymes were known to be present, the placenta was previously considered incapable of glucose secretion because it lacked functional glucose-6-phosphatase. Recent studies, however, have suggested that specific glucose-6-phosphatase may be present in placenta but it may be the product of a different gene from conventional hepatic glucose-6-phosphatase. The presence of the specific transporters necessary for glucose-6-phosphatase activity is currently being investigated. The role of placental glucose secretion in normal and growth-restricted pregnancies is an area of current study.

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The two expressed genes coding for N-acetyltransferase (NAT) activity, NAT1 and NAT2, are located on chromosome 8 at 8p21.3-23.1 and are polymorphic. Both enzymes are capable of N-acetylation, O-acetylation, and N,O-acetylation and are implicated in the activation and detoxification of known carcinogens. Single base-pair substitutions in NAT2 tend to occur in combination with other substitutions within the gene. As yet, less work has been done to characterize NAT1 allelic variants. Various methods for the detection of the reported polymorphisms exist. It is important to select a method that is appropriate to the population being studied. The functional significance of many NAT allelic variants has not been determined. Geographic and ethnic variation in the frequency of NAT2 genotypes associated with fast or intermediate acetylation has been observed. Insufficient data for NAT1 genotypes are available to reveal a clear geographic pattern. No consistent association has been found between acetylator phenotype or genotype and colorectal cancer. The lack of consistency can in part be accounted for by methodological factors, including limited statistical power. Possible interactions between the NAT genes and either environmental exposures or other polymorphic genes encoding xenobiotic metabolizing enzymes have been investigated in only a minority of these studies, and these studies have lacked statistical power to detect interactions.

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The genes glutathione S-transferase M1 (GSTM1) (chromosome 1p13.3) and glutathione S-transferase T1 (GSTT1) (22q11.2) code for cytosolic enzymes glutathione S-transferase (GST)-mu and GST-theta, respectively, which are involved in phase 2 metabolism. Both genes may be deleted. There is geographic and ethnic variation in genotype frequencies for both genes. In developed countries, colorectal cancer is the second most common cancer. Colorectal cancer has been inconsistently associated with polycyclic aromatic hydrocarbons in diet and tobacco. Because GST enzymes are involved in polycyclic aromatic hydrocarbon metabolism, it has been postulated that genotype may modify colorectal cancer risk associated with polycyclic aromatic hydrocarbon exposure. No consistent associations between GSTM1 or GSTT1 genotype and colorectal cancer have been observed. However, most studies have methodological limitations. Few have investigated gene-environment interactions. No interactions between GSTM1 or GSTT1 genotype and smoking and colorectal cancer risk have been reported. One polyp study suggests an interaction between GSTM1 genotype and smoking. Two studies suggest increased disease risk in subjects with high meat intake and GST nonnull genotype, contrary to the underlying hypothesis. One study suggests a strong inverse relation between colorectal adenomas and broccoli consumption, particularly in subjects who are GSTM1 null. These finding require confirmation. Methods for determining GSTM1 and GSTT1 genotype are well established. Population testing is not currently justified.

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