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

Grolleman, J. E., de Voer, R. M., Elsayed, F. A., Nielsen, M., Weren, R. D. A., Palles, C., Ligtenberg, M. J. L., Vos, J. R., ten Broeke, S. W., de Miranda, N. F. C. C., Kuiper, R. A., Kamping, E. J., Jansen, E. A. M., Vink-Borger, M. E., Popp, I., Lang, A., Spier, I., Hueneburg, R., James, P. A., Li, N., Staninova, M., Lindsay, H., Cockburn, D., Spasic-Boskovic, O., Clendenning, M., Sweet, K., Capella, G., Sjursen, W., Hoberg-Vetti, H., Jongmans, M. C., Neveling, K., van Kessel, A. G., Morreau, H., Hes, F. J., Sijmons, R. H., Schackert, H. K., Ruiz-Ponte, C., Dymerska, D., Lubinski, J., Rivera, B., Foulkes, W. D., Tomlinson, I. P., Valle, L., Buchanan, D. D., Kenwrick, S., Adlard, J., Dimovski, A. J., Campbell, I. G., Aretz, S. & Kuiper, R. P., 11-Feb-2019, In : Cancer cell. 35, 2, p. 256-266.e5 16 p.

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  • Judith E. Grolleman
  • Richarda M. de Voer
  • Fadwa A. Elsayed
  • Maartje Nielsen
  • Robbert D. A. Weren
  • Claire Palles
  • Marjolijn J. L. Ligtenberg
  • Janet R. Vos
  • Sanne W. ten Broeke
  • Noel F. C. C. de Miranda
  • Renske A. Kuiper
  • Eveline J. Kamping
  • Erik A. M. Jansen
  • M. Elisa Vink-Borger
  • Isabell Popp
  • Alois Lang
  • Isabel Spier
  • Robert Hueneburg
  • Paul A. James
  • Na Li
  • Marija Staninova
  • Helen Lindsay
  • David Cockburn
  • Olivera Spasic-Boskovic
  • Mark Clendenning
  • Kevin Sweet
  • Gabriel Capella
  • Wenche Sjursen
  • Hildegunn Hoberg-Vetti
  • Marjolijn C. Jongmans
  • Kornelia Neveling
  • Ad Geurts van Kessel
  • Hans Morreau
  • Frederik J. Hes
  • Rolf H. Sijmons
  • Hans K. Schackert
  • Clara Ruiz-Ponte
  • Dagmara Dymerska
  • Jan Lubinski
  • Barbara Rivera
  • William D. Foulkes
  • Ian P. Tomlinson
  • Laura Valle
  • Daniel. D. Buchanan
  • Sue Kenwrick
  • Julian Adlard
  • Aleksandar J. Dimovski
  • Ian G. Campbell
  • Stefan Aretz
  • Roland P. Kuiper

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
Number of pages16
JournalCancer cell
Issue number2
Publication statusPublished - 11-Feb-2019



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