Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.
Grolleman JE., de Voer RM., Elsayed FA., Nielsen M., Weren RDA., Palles C., Ligtenberg MJL., Vos JR., Ten Broeke SW., de Miranda NFCC., Kuiper RA., Kamping EJ., Jansen EAM., Vink-Börger ME., Popp I., Lang A., Spier I., Hüneburg R., James PA., Li N., Staninova M., Lindsay H., Cockburn D., Spasic-Boskovic O., Clendenning M., Sweet K., Capellá G., Sjursen W., Høberg-Vetti H., Jongmans MC., Neveling K., Geurts van Kessel A., Morreau H., Hes FJ., Sijmons RH., Schackert HK., Ruiz-Ponte C., Dymerska D., Lubinski J., Rivera B., Foulkes WD., Tomlinson IP., Valle L., Buchanan DD., Kenwrick S., Adlard J., Dimovski AJ., Campbell IG., Aretz S., Schindler D., van Wezel T., Hoogerbrugge N., Kuiper RP.
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.