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A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer

Nature Genetics volume 47, pages 668–671 (2015)Cite this article

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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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Figure 1: Pedigrees of the families with individuals homozygous for the NTHL1 mutation encoding p.Gln90*.
Figure 2: Mutation spectra of adenomas and carcinomas derived from individuals homozygous for the NTHL1 mutation encoding p.Gln90*.

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References

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Dallosso, A.R. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  12. Cooke, M.S., Evans, M.D., Dizdaroglu, M. & Lunec, J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 17, 1195–1214 (2003).

    Article  CAS  Google Scholar 

  13. Chan, M.K. 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).

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  20. O'Roak, B.J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012).

    Article  CAS  Google Scholar 

  21. Boyle, E.A., O'Roak, B.J., Martin, B.K., Kumar, A. & Shendure, J. MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics 30, 2670–2672 (2014).

    Article  CAS  Google Scholar 

  22. Hiatt, J.B., Pritchard, C.C., Salipante, S.J., O'Roak, B.J. & Shendure, J. Single molecule molecular inversion probes for targeted, high-accuracy detection of low-frequency variation. Genome Res. 23, 843–854 (2013).

    Article  CAS  Google Scholar 

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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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  1. Roland P Kuiper and Nicoline Hoogerbrugge: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Roland P Kuiper.

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The authors declare no competing financial interests.

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Supplementary Tables 1–10 and Supplementary Figures 1–6. (PDF 2347 kb)

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Weren, R., Ligtenberg, M., Kets, C. et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet 47, 668–671 (2015). https://doi.org/10.1038/ng.3287

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