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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.



  1. 1.

    et al. Patterns of somatic mutation in human cancer genomes. Nature 446, 153–158 (2007).

  2. 2.

    et al. Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat. Genet. 30, 227–232 (2002).

  3. 3.

    et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat. Genet. 45, 136–144 (2013).

  4. 4.

    & Germline and somatic polymerase ɛ and δ mutations define a new class of hypermutated colorectal and endometrial cancers. J. Pathol. 230, 148–153 (2013).

  5. 5.

    et al. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res. 63, 7595–7599 (2003).

  6. 6.

    et al. Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists. Clin. Genet. 81, 38–46 (2012).

  7. 7.

    Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014).

  8. 8.

    et al. Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut 57, 1252–1255 (2008).

  9. 9.

    et al. Role of the oxidative DNA damage repair gene OGG1 in colorectal tumorigenesis. J. Natl. Cancer Inst. 105, 1249–1253 (2013).

  10. 10.

    et al. Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition. BMC Cancer 6, 243 (2006).

  11. 11.

    et al. Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer 9, 184 (2009).

  12. 12.

    , , & Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195–1214 (2003).

  13. 13.

    et al. Targeted deletion of the genes encoding NTH1 and NEIL1 DNA N-glycosylases reveals the existence of novel carcinogenic oxidative damage to DNA. DNA Repair (Amst.) 8, 786–794 (2009).

  14. 14.

    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

  15. 15.

    et al. Genetic variation in the base excision repair pathway, environmental risk factors, and colorectal adenoma risk. PLoS ONE 8, e71211 (2013).

  16. 16.

    et al. Exome sequencing identifies WDR35 variants involved in Sensenbrenner syndrome. Am. J. Hum. Genet. 87, 418–423 (2010).

  17. 17.

    International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  18. 18.

    et al. Autozygosity mapping with exome sequence data. Hum. Mutat. 34, 50–56 (2013).

  19. 19.

    et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).

  20. 20.

    et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

  21. 21.

    , , , & MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics 30, 2670–2672 (2014).

  22. 22.

    , , , & Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23, 843–854 (2013).

Download references


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).

Author information

Author notes

    • Roland P Kuiper
    •  & Nicoline Hoogerbrugge

    These authors contributed equally to this work.


  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


  1. Search for Robbert D A Weren in:

  2. Search for Marjolijn J L Ligtenberg in:

  3. Search for C Marleen Kets in:

  4. Search for Richarda M de Voer in:

  5. Search for Eugène T P Verwiel in:

  6. Search for Liesbeth Spruijt in:

  7. Search for Wendy A G van Zelst-Stams in:

  8. Search for Marjolijn C Jongmans in:

  9. Search for Christian Gilissen in:

  10. Search for Jayne Y Hehir-Kwa in:

  11. Search for Alexander Hoischen in:

  12. Search for Jay Shendure in:

  13. Search for Evan A Boyle in:

  14. Search for Eveline J Kamping in:

  15. Search for Iris D Nagtegaal in:

  16. Search for Bastiaan B J Tops in:

  17. Search for Fokko M Nagengast in:

  18. Search for Ad Geurts van Kessel in:

  19. Search for J Han J M van Krieken in:

  20. Search for Roland P Kuiper in:

  21. Search for Nicoline Hoogerbrugge in:


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.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Tables 1–10 and Supplementary Figures 1–6.

About this article

Publication history






Further reading