Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Research output: Contribution to journalArticleAcademicpeer-review


Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

Original languageEnglish
Pages (from-to)256-266.e5
JournalCancer Cell
Issue number2
Publication statusPublished - 11 Feb 2019


  • adenomatous polyposis
  • base excision repair
  • breast cancer
  • colorectal cancer
  • DNA repair defect
  • genetic predisposition
  • multiple malignancies
  • mutational signature
  • NTHL1
  • somatic mutation spectrum


Dive into the research topics of 'Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype'. Together they form a unique fingerprint.

Cite this