title: Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency.
abstract: 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.
authors.affiliation: Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, V Uvalu 84, 15006 Prague 5, Czech Republic. pevas78@hotmail.com
authors.forename: P
authors.initials: P
authors.lastname: Vasovcak
authors.forename: A
authors.initials: A
authors.lastname: Krepelova
authors.forename: M
authors.initials: M
authors.lastname: Menigatti
authors.forename: A
authors.initials: A
authors.lastname: Puchmajerova
authors.forename: P
authors.initials: P
authors.lastname: Skapa
authors.forename: A
authors.initials: A
authors.lastname: Augustinakova
authors.forename: G
authors.initials: G
authors.lastname: Amann
authors.forename: A
authors.initials: A
authors.lastname: Wernstedt
authors.forename: J
authors.initials: J
authors.lastname: Jiricny
authors.forename: G
authors.initials: G
authors.lastname: Marra
authors.forename: K
authors.initials: K
authors.lastname: Wimmer
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics; D000293:Adolescent; D000595:Amino Acid Sequence; D045643:DNA Repair Enzymes / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000070976:Mismatch Repair Endonuclease PMS2; D008969:Molecular Sequence Data; D010641:Phenotype; D012004:Rectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D044502:Thymine DNA Glycosylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D044502:Thymine DNA Glycosylase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes