Lack of DMBT1 expression in oesophageal, gastric and colon cancers

Loss of sequences from human chromosome 10q has been reported in several different cancers. Recently, a second candidate tumour-suppressor gene, DMBT1, was identified in this chromosomal region. We studied the mRNA expression and homozygous deletion of this gene in human oesophageal, gastric and colon cancers. Reverse transcriptase polymerase chain reaction (RT-PCR) amplification demonstrated that 23 (53.5%) of 43 oesophageal, 5 (12.5%) of 40 gastric, and 4 (16.7%) of 24 colorectal cancer cases showed an apparent reduction in DMBT1 mRNA in tumour tissues compared with paired normal tissues. Twelve out of 15 oesophageal cancer cell lines also showed no expression. We next studied homozygous deletions within the DMBT1 gene in oesophageal cancers by using duplex PCR. Consequently, it was recognized in five (11.6%) of the primary tumours and two (13.3%) of the cell lines. These findings suggest that DMBT1 may act as a tumour-suppressor gene not only in brain tumours but also in gastrointestinal cancers, especially in oesophageal cancers. © 1999 Cancer Research Campaig

Mutation and deletion analysis of GFRα-1, encoding the co-receptor for the GDNF/RET complex, in human brain tumours

Glial cell line-derived neurotrophic factor (GDNF) plays a key role in the control of vertebrate neuron survival and differentiation in both the central and peripheral nervous systems. GDNF preferentially binds to GFRα-1 which then interacts with the receptor tyrosine kinase RET. We investigated a panel of 36 independent cases of mainly advanced sporadic brain tumours for the presence of mutations in GDNF and GFRα-1. No mutations were found in the coding region of GDNF. We identified six previously described GFRα-1 polymorphisms, two of which lead to an amino acid change. In 15 of 36 brain tumours, all polymorphic variants appeared to be homozygous. Of these 15 tumours, one also had a rare, apparently homozygous, sequence variant at codon 361. Because of the rarity of the combination of homozygous sequence variants, analysis for hemizygous deletion was pursued in the 15 samples and loss of heterozygosity was found in 11 tumours. Our data suggest that intragenic point mutations of GDNF or GFRα-1 are not a common aetiologic event in brain tumours. However, either deletion of GFRα-1 and/or nearby genes may contribute to the pathogenesis of these tumours

Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma

We examined a panel of sporadic breast carcinomas for loss of heterozygosity (LOH) in a 10-cM interval on chromosome 10 known to encompass the PTEN gene. We detected allele loss in 27 of 70 breast tumour DNAs. Fifteen of these showed loss limited to a subregion of the area studied. The most commonly deleted region was flanked by D10S215 and D10S541 and encompasses the PTEN locus. We used a combination of denaturing gradient gel electrophoresis and single-strand conformation polymorphism analyses to investigate the presence of PTEN mutations in tumours with LOH in this region. We did not detect mutations of PTEN in any of these tumours. Our data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not. These results are consistent with loss of another unidentified tumour suppressor in this region in sporadic breast carcinoma. © 1999 Cancer Research Campaig

Dietary fat, insulin sensitivity and the metabolic syndrome

Insulin resistance is the pathogenetic link underlying the different metabolic abnormalities clustering in the metabolic syndrome. It can be induced by different environmental factors, including dietary habits. Consumption of energy-dense/high fat diets is strongly and positively associated with overweight that, in turn, deteriorates insulin sensitivity, particularly when the excess of body fat is located in abdominal region. Nevertheless the link between fat intake and overweight is not limited to the high-energy content of fatty foods; the ability to oxidize dietary fat is impaired in some individuals genetically predisposed to obesity. Insulin sensitivity is also affected by the quality of dietary fat, independently of its effects on body weight. Epidemiological evidence and intervention studies clearly show that in humans saturated fat significantly worsen insulin-resistance, while monounsaturated and polyunsaturated fatty acids improve it through modifications in the composition of cell membranes which reflect at least in part dietary fat composition. A recent multicenter study (KANWU) has shown that shifting from a diet rich in saturated fatty acids to one rich in monounsaturated fat improves insulin sensitivity in healthy people while a moderate alpha-3 fatty acids supplementation does not affect insulin sensitivity. There are also other features of the metabolic syndrome that are influenced by different types of fat, particularly blood pressure and plasma lipid levels. Most studies show that alpha-3 fatty acids reduce blood pressure in hypertensive but not in normotensive subjects while shifting from saturated to monounsaturated fat intake reduces diastolic blood pressure. In relation to lipid abnormalities alpha-3 fatty acids reduce plasma triglyceride levels but in parallel, increase LDL cholesterol. Substitution of unsaturated fat for saturated fat not only reduces LDL cholesterol but contributes also to reduce plasma triglycerides in insulin resistant individuals. In conclusion, there is evidence available in humans indicating that dietary fat quality influences insulin sensitivity and associated metabolic abnormalities. Therefore, prevention of the metabolic syndrome has to be targeted: (1) to correct overweight by reducing the energy density of the habitual diet (i.e., fat intake) and (2) to improve insulin sensitivity and associated metabolic abnormalities through a reduction of dietary saturated fat, partially replaced, when appropriate, by monounsaturated and polyunsaturated fats