title: Analysis of the oxidative damage repair genes NUDT1, OGG1, and MUTYH in patients from mismatch repair proficient HNPCC families (MSS-HNPCC).
abstract: OBJECTIVE
  Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1.
  
  
  METHODS
  We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families.
  
  
  RESULTS
  Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1.
  
  
  CONCLUSIONS
  Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.
authors.affiliation: Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, Madrid, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Garre
authors.forename: Verónica
authors.initials: V
authors.lastname: Briceño
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Xicola
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Doyle
authors.forename: Miguel
authors.initials: M
authors.lastname: de la Hoya
authors.forename: Julián
authors.initials: J
authors.lastname: Sanz
authors.forename: Patricia
authors.initials: P
authors.lastname: Llovet
authors.forename: Paula
authors.initials: P
authors.lastname: Pescador
authors.forename: Javier
authors.initials: J
authors.lastname: Puente
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
authors.forename: Xavier
authors.initials: X
authors.lastname: Llor
authors.forename: Trinidad
authors.initials: T
authors.lastname: Caldés
mesh_terms: D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics*; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017354:Point Mutation; D015183:Restriction Mapping; D017422:Sequence Analysis, DNA
chemical_list: D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes