The analysis of PIK3CA mutations in gastric carcinoma and metanalysis of literature suggest that exon-selectivity is a signature of cancer type.

BACKGROUND: PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. METHODS: We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. RESULTS: The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and their clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions presented in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. CONCLUSIONS: The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise.

Association of polymorphisms in the IL1B and IL2 genes with susceptibility and severity of systemic sclerosis.

OBJECTIVE: To investigate possible associations of 9 single-nucleotide polymorphisms in the IL10, IL1B, IL1A, IL1RN, IL2, LTA, and IL6 genes with susceptibility to systemic sclerosis (SSc), and with clinical subtype of SSc patients. METHODS: A total of 78 patients with SSc [diffuse SSc (dcSSc), n = 31; limited SSc, (lcSSc), n = 47] and 692 healthy blood donors were genotyped for the following polymorphisms: IL10 T-3575A, IL10 A-1082G, IL1B C-31T, IL1B C-511T, IL1A C-889T, IL1RN A9589T, IL2 T-384G, LTA T-91G, and IL6 G-174C. RESULTS: Alleles in IL1B-31 and IL1B-511 showed a significantly different distribution between cases and controls. Carriers of at least one copy of the IL1B-31-C allele had an increased risk of SSc [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6-5.2, p < 0.001], while a similar strong association was also evident for IL1B-511-T carriers (OR 3.1, 95% CI 1.7-5.7, p < 0.001). Interestingly, carriers of the IL2-384-G allele were significantly more frequent among patients with lcSSc (80.8%), compared to patients with the diffuse subtype (45.1%) (OR 5.1, 95% CI 1.8-14.3, p = 0.001) and in subjects positive to anticentromere antibodies (OR 4.2, 95% CI 1.5-11.9, p = 0.007). Lastly, the distribution of the IL2-384 genotype showed statistically significant differences between controls and patients with lcSSc (OR 3.5, 95% CI 1.7-7.4, p < 0.001). There were no differences between patients with dcSSc and controls. CONCLUSION: IL1B and IL2 gene polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele may be a marker for the limited phenotype of SSc.

Effect of urban traffic, individual habits, and genetic polymorphisms on background urinary 1-hydroxypyrene excretion.

PURPOSE: Potential sources of exposure to polycyclic aromatic hydrocarbons (PAHs) and genetic polymorphisms were investigated in relation to their contribution to interindividual variation in baseline levels of urinary 1-hydroxypyrene (1-OHP) excretion in subjects without occupational exposure to PAHs. METHODS: Urinary excretion of 1-OHP was measured in 114 subjects, including 48 women and 66 men. Questionnaire information was collected on possible environmental and individual sources of PAH exposure. A subset of 70 individuals also was evaluated for a single-nucleotide polymorphism (Ex7+295C-->T) in the cytochrome P-450 1A2 (CYP1A2) gene, and 61 of these also were evaluated for the glutathione transferase T1 (GSTT1) gene polymorphism. RESULTS: 1-OHP values did not show a significant seasonal variability and were unaffected by age; education; body mass index; smoking status, including passive smoking; or the C-->T base substitution in position 295 of exon 7 of the CYP1A2 gene. After reciprocal adjustment with logistic regression, living in a heavily trafficked urban area (odds ratio, 4.9; 95% confidence interval, 1.0-24.9), and frequent intake of grilled meat (odds ratio, 6.9; 95% confidence interval, 1.1-43.5) were significant predictors of background urinary 1-OHP levels of 0.50 microg/g creatinine or greater. Elevated risks also were associated with daily alcohol intake greater than 65 g and the nonnull GSTT1 genotype. CONCLUSION: Our study shows that exposure to urban traffic, dietary habits, and the nonnull GSTT1 genotype may contribute to interindividual variation in background levels of 1-OHP urinary excretion in subjects without occupational exposure to PAHs.