| Literature DB >> 30753826 |
Judith E Grolleman1, Richarda M de Voer2, Fadwa A Elsayed3, Maartje Nielsen4, Robbert D A Weren1, Claire Palles5, Marjolijn J L Ligtenberg6, Janet R Vos7, Sanne W Ten Broeke4, Noel F C C de Miranda3, Renske A Kuiper1, Eveline J Kamping1, Erik A M Jansen1, M Elisa Vink-Börger8, Isabell Popp9, Alois Lang10, Isabel Spier11, Robert Hüneburg12, Paul A James13, Na Li14, Marija Staninova15, Helen Lindsay16, David Cockburn16, Olivera Spasic-Boskovic17, Mark Clendenning18, Kevin Sweet19, Gabriel Capellá20, Wenche Sjursen21, Hildegunn Høberg-Vetti22, Marjolijn C Jongmans1, Kornelia Neveling1, Ad Geurts van Kessel1, Hans Morreau3, Frederik J Hes4, Rolf H Sijmons23, Hans K Schackert24, Clara Ruiz-Ponte25, Dagmara Dymerska26, Jan Lubinski26, Barbara Rivera27, William D Foulkes28, Ian P Tomlinson29, Laura Valle20, Daniel D Buchanan30, Sue Kenwrick17, Julian Adlard31, Aleksandar J Dimovski15, Ian G Campbell14, Stefan Aretz11, Detlev Schindler9, Tom van Wezel3, Nicoline Hoogerbrugge1, Roland P Kuiper32.
Abstract
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.Entities:
Keywords: DNA repair defect; NTHL1; adenomatous polyposis; base excision repair; breast cancer; colorectal cancer; genetic predisposition; multiple malignancies; mutational signature; somatic mutation spectrum
Year: 2019 PMID： 30753826 DOI： 10.1016/j.ccell.2018.12.011
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743