Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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 publication




Journal article


Cancer cell

Publication Date





256 - 266.e5


Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.


Humans, Neoplastic Syndromes, Hereditary, Genetic Predisposition to Disease, Deoxyribonuclease (Pyrimidine Dimer), Risk Assessment, Risk Factors, Gene Expression Profiling, Pedigree, DNA Mutational Analysis, DNA Repair, Gene Expression Regulation, Neoplastic, Heredity, Phenotype, Germ-Line Mutation, Adult, Aged, Middle Aged, Europe, Female, Male, Young Adult, Transcriptome, Biomarkers, Tumor