Germline variation in the oxidative DNA repair genes NUDT1 and OGG1 is not associated with hereditary colorectal cancer or polyposis

Hum Mutat. 2018 Sep;39(9):1214-1225. doi: 10.1002/humu.23564. Epub 2018 Jul 4.

Abstract

The causal association of NUDT1 (=MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here, we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next-generation sequencing in 529 families (441 uncharacterized MMR-proficient familial nonpolyposis CRC and 88 polyposis cases). Cosegregation, in silico analyses, in vitro functional assays, and case-control associations were carried out to characterize the identified variants. Five heterozygous carriers of novel (n = 1) or rare (n = 4) NUDT1 variants were identified. In vitro deleterious effects were demonstrated for c.143G>A p.G48E (catalytic activity and protein stability) and c.403G>T p.G135W (protein stability), although cosegregation data in the carrier families were inconclusive or nonsupportive. The frequency of missense, loss-of-function, and splice-site NUDT1 variants in our familial CRC cohort was similar to the one observed in cancer-free individuals, suggesting lack of association with CRC predisposition. No OGG1 pathogenic mutations were identified. Our results suggest that the contribution of NUDT1 and OGG1 germline mutations to hereditary CRC and to polyposis is inexistent or, at most, negligible. The inclusion of these genes in routine genetic testing is not recommended.

Keywords: MTH1; NUDT1; OGG1; base excision repair; colorectal cancer predisposition; genetic testing; germline mutation; hereditary cancer; oxidative DNA repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics*
  • Adenomatous Polyposis Coli / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Glycosylases / genetics*
  • DNA Repair / genetics
  • DNA Repair Enzymes / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genetic Variation / genetics
  • Genotype
  • Germ-Line Mutation / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Loss of Function Mutation / genetics
  • Male
  • Mutation, Missense / genetics
  • Oxidative Stress
  • Phosphoric Monoester Hydrolases / genetics*
  • Protein Isoforms / genetics

Substances

  • Protein Isoforms
  • Phosphoric Monoester Hydrolases
  • DNA Glycosylases
  • oxoguanine glycosylase 1, human
  • 8-oxodGTPase
  • DNA Repair Enzymes