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Highlights ► We characterized the mutator phenotype of a very early onset rectal cancer. ► High frequency of C:G>T:A or G:C>A:T transitions at methylated CpG sites was found. ► A somatic TDG mutation was found associated with TDG expression loss in the tumor. ► 1st in vivo evidence that TDG acts against deleterious 5-methylcytosine deamination., Cells with DNA repair defects have increased genomic instability and are more likely to acquire secondary mutations that bring about cellular transformation. We describe the frequency and spectrum of somatic mutations involving several tumor suppressor genes in the rectal carcinoma of a 13-year-old girl harboring biallelic, germline mutations in the DNA mismatch repair gene PMS2. Apart from microsatellite instability, the tumor DNA contained a number of C:G → T:A or G:C → A:T transitions in CpG dinucleotides, which often result through spontaneous deamination of cytosine or 5-methylcytosine. Four DNA glycosylases, UNG2, SMUG1, MBD4 and TDG, are involved in the repair of these deamination events. We identified a heterozygous missense mutation in TDG, which was associated with TDG protein loss in the tumor. The CpGs mutated in this patient's tumor are generally methylated in normal colonic mucosa. Thus, it is highly likely that loss of TDG contributed to the supermutator phenotype and that most of the point mutations were caused by deamination of 5-methylcytosine to thymine, which remained uncorrected owing to the TDG deficiency. This case provides the first in vivo evidence of the key role of TDG in protecting the human genome against the deleterious effects of 5-methylcytosine deamination.

Background: The authors evaluate the prevalence of Helicabacter pylori resistance in 117 children and demonstrate the changes over a 4-year period. Methods: In 117 children and adolescents, H. pylori-positive gastritis was revealed by diagnostic upper endoscopy. Biopsies from the antrum and body of the stomach were tested by histology, urease test, and culture. H. pylori was isolated using standard culture techniques, and susceptibility to amoxicillin, clarithromycin, and metronidazole was tested using the E-test (AB-Biodisk, Sweden). Results: Endoscopy revealed gastric ulcers in 2 of 117 subjects, duodenal ulcers in 6 of 117, and erosive gastritis or duodenitis in 23 of 117. Almost all patients showed antral nodularity. Histology always showed chronic gastritis with different degrees of activity. During the 4-year study period, the authors noticed an increase of primary clarithromycin-resistant H. pylori strains, from 14.3% to 27.6% (mean, 20.3%). Metronidazole resistance varied between 5% and 25%. No resistance to amoxicillin was found. Conclusion: Eradication of H. pylori should take place only after testing of susceptibility. The general use of clarithromycin in children should be restricted to better-defined indications. Resistance to clarithromycin of H. pylori may also become a future problem for the treatment of adults.

In late 1990 a screening program for the early detection of neuroblastoma in infants was introduced in Austria. The program is performed on a voluntary basis in collaboration with general pediatricians and practitioners. Filter strips for urine collection are distributed to parents of infants aged seven to nine months on the occasion of a routine check up. The samples are sent to the laboratory by parents and analysed for vanillylmandelic acid (VMA) and homovanillic acid (HVA). Between January 1991 and December 1995 125,201 infants were screened. The compliance rate was 26.8% for Austria, but great differences were seen for different regions (65% in Carinthia, 10% in Vorarlberg). 30 children were admitted to hospital for investigation of repeatedly elevated urine catecholamines. A neuroblastoma was identified in 16 cases. In 12 of these cases at least one unfavorable prognostic factor was present (stageor = 3, elevated LDH, unfavorable histology, N-myc amplification, di- or tetraploidy). Neuroblastoma screening of infants aged more than six months seems to detect predominantly those tumors which are unlikely to regress spontaneously. The observation of one false negative case, however, demonstrates that neuroblastomas which become clinically manifest at a later date may remain undetected by early screening. Possible advantages of shifting screening to a later age and repeated screening are discussed.