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

• Published in: Cancer cell Vol. 35; no. 2; pp. 256 - 266.e5
• Main Authors: Grolleman, Judith E., de Voer, Richarda M., Elsayed, Fadwa A., Nielsen, Maartje, Weren, Robbert D.A., Palles, Claire, Ligtenberg, Marjolijn J.L., Vos, Janet R., ten Broeke, Sanne W., de Miranda, Noel F.C.C., Kuiper, Renske A., Kamping, Eveline J., Jansen, Erik A.M., Vink-Börger, M. Elisa, Popp, Isabell, Lang, Alois, Spier, Isabel, Hüneburg, Robert, James, Paul A., Li, Na, Staninova, Marija, Lindsay, Helen, Cockburn, David, Spasic-Boskovic, Olivera, Clendenning, Mark, Sweet, Kevin, Capellá, Gabriel, Sjursen, Wenche, Høberg-Vetti, Hildegunn, Jongmans, Marjolijn C., Neveling, Kornelia, Geurts van Kessel, Ad, Morreau, Hans, Hes, Frederik J., Sijmons, Rolf H., Schackert, Hans K., Ruiz-Ponte, Clara, Dymerska, Dagmara, Lubinski, Jan, Rivera, Barbara, Foulkes, William D., Tomlinson, Ian P., Valle, Laura, Buchanan, Daniel. D., Kenwrick, Sue, Adlard, Julian, Dimovski, Aleksandar J., Campbell, Ian G., Aretz, Stefan, Schindler, Detlev, van Wezel, Tom, Hoogerbrugge, Nicoline, Kuiper, Roland P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.02.2019
• Subjects: adenomatous polyposis; Adult; Aged; base excision repair; Biomarkers, Tumor - deficiency; Biomarkers, Tumor - genetics; breast cancer; colorectal cancer; Deoxyribonuclease (Pyrimidine Dimer) - deficiency; Deoxyribonuclease (Pyrimidine Dimer) - genetics; DNA Mutational Analysis; DNA Repair - genetics; DNA repair defect; Europe; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; genetic predisposition; Genetic Predisposition to Disease; Germ-Line Mutation; Heredity; Humans; Male; Middle Aged; multiple malignancies; mutational signature; Neoplastic Syndromes, Hereditary - enzymology; Neoplastic Syndromes, Hereditary - genetics; Neoplastic Syndromes, Hereditary - pathology; NTHL1; Pedigree; Phenotype; Risk Assessment; Risk Factors; somatic mutation spectrum; Transcriptome; Young Adult; Europe; adenomatous polyposis; colorectal cancer; somatic mutation spectrum; NTHL1; base excision repair; genetic predisposition; DNA repair defect; breast cancer; multiple malignancies; mutational signature
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.12.011

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. [Display omitted] •Biallelic germline NTHL1 mutations predispose to a multi-tumor syndrome•Biallelic germline NTHL1 mutation carriers are at risk for breast cancer•Tumors from NTHL1-deficient patients reveal a cross-cancer NTHL1-associated signature•Mutational signature analyses can assist to identify germline DNA repair defects In addition to the know colorectal tumors, Grolleman et al. find tumors in 13 tissue types, including a high breast cancer incidence, among 29 carriers of biallelic germline NTHL1 mutations and identify a mutation signature across tumor types, which may facilitate the identification and management of new cases.