Abstract

The genetic cause underlying the development of multiple colonic adenomas, the premalignant precursors of colorectal cancer (CRC), frequently remains unresolved in patients with adenomatous polyposis. Here we applied whole-exome sequencing to 51 individuals with multiple colonic adenomas from 48 families. In seven affected individuals from three unrelated families, we identified a homozygous germline nonsense mutation in the base-excision repair (BER) gene NTHL1. This mutation was exclusively found in a heterozygous state in controls (minor allele frequency of 0.0036; n = 2,329). All three families showed recessive inheritance of the adenomatous polyposis phenotype and progression to CRC in at least one member. All three affected women developed an endometrial malignancy or premalignancy. Genetic analysis of three carcinomas and five adenomas from different affected individuals showed a non-hypermutated profile enriched for cytosine-to-thymine transitions. We conclude that a homozygous loss-of-function germline mutation in the NTHL1 gene predisposes to a new subtype of BER-associated adenomatous polyposis and CRC.

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Acknowledgements

We thank N. Arts, A. van Raaij, S. van Vliet, M. van de Vorst and M. Kwint for technical assistance, and R. Derks and M. Nelen for targeted tumor sequencing and data analysis. We thank H. Brunner for critical reading of the manuscript. The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at http://exac.broadinstitute.org/about. This work was supported by research grants from the Dutch Cancer Society (KWF; grant 2009-4335) and the Netherlands Organization for Scientific Research (NWO; grant 917-10-358).

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Author notes

    • Roland P Kuiper
    •  & Nicoline Hoogerbrugge

    These authors contributed equally to this work.

Affiliations

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

    • Robbert D A Weren
    • , Marjolijn J L Ligtenberg
    • , C Marleen Kets
    • , Richarda M de Voer
    • , Eugène T P Verwiel
    • , Liesbeth Spruijt
    • , Wendy A G van Zelst-Stams
    • , Marjolijn C Jongmans
    • , Christian Gilissen
    • , Jayne Y Hehir-Kwa
    • , Alexander Hoischen
    • , Eveline J Kamping
    • , Ad Geurts van Kessel
    • , Roland P Kuiper
    •  & Nicoline Hoogerbrugge
  2. Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Marjolijn J L Ligtenberg
    • , Iris D Nagtegaal
    • , Bastiaan B J Tops
    •  & J Han J M van Krieken
  3. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Jay Shendure
    •  & Evan A Boyle
  4. Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands.

    • Fokko M Nagengast

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Contributions

R.D.A.W., R.P.K. and N.H. designed the study. R.D.A.W. analyzed and interpreted whole-exome sequencing data. R.D.A.W., R.M.d.V. and E.J.K. performed laboratory experiments and/or analyzed data. E.T.P.V. and J.Y.H.-K. performed haploblock analysis. R.D.A.W. and B.B.J.T. performed somatic mutation analyses. C.G. supervised bioinformatics data assembly and performed statistical analysis. J.S., E.A.B. and A.H. designed molecular inversion probes. I.D.N. and J.H.J.M.v.K. collected tumor samples and interpreted histology. C.M.K., L.S., W.A.G.v.Z.-S., M.C.J., F.M.N. and N.H. were responsible for patient counseling and clinical data acquisition. M.J.L.L., A.G.v.K., R.P.K. and N.H. supervised the work. R.D.A.W., R.P.K. and N.H. wrote the manuscript, with assistance and final approval from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Roland P Kuiper.

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DOI

https://doi.org/10.1038/ng.3287

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