A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Robbert D A Weren, Marjolijn J L Ligtenberg, C Marleen Kets, Richarda M de Voer, Eugène T P Verwiel, Liesbeth Spruijt, Wendy A G van Zelst-Stams, Marjolijn C Jongmans, Christian Gilissen, Jayne Y Hehir-Kwa, Alexander Hoischen, Jay Shendure, Evan A Boyle, Eveline J Kamping, Iris D Nagtegaal, Bastiaan B J Tops, Fokko M Nagengast, Ad Geurts van Kessel, J Han J M van Krieken, Roland P KuiperNicoline Hoogerbrugge

Research output: Contribution to journalArticlepeer-review

284 Citations (Scopus)


The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

Original languageEnglish
Pages (from-to)668-71
Number of pages4
JournalNature Genetics
Issue number6
Publication statusPublished - Jun 2015
Externally publishedYes


  • Adenomatous Polyposis Coli/genetics
  • Case-Control Studies
  • Codon, Nonsense
  • DNA Mutational Analysis
  • DNA Repair
  • Deoxyribonuclease (Pyrimidine Dimer)/genetics
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Homozygote
  • Humans
  • Middle Aged
  • Pedigree


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