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Original article
Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis
  1. Frederik J Hes1,
  2. Dina Ruano2,
  3. Marry Nieuwenhuis3,
  4. Carli M Tops1,
  5. Melanie Schrumpf2,
  6. Maartje Nielsen1,
  7. Petra E A Huijts4,
  8. Juul T Wijnen1,4,
  9. Anja Wagner5,
  10. Encarna B Gómez García6,
  11. Rolf H Sijmons7,
  12. Fred H Menko8,
  13. Tom G W Letteboer9,
  14. Nicoline Hoogerbrugge10,
  15. Jan Harryvan11,
  16. Ellen Kampman11,
  17. Hans Morreau2,
  18. Hans F A Vasen3,12,
  19. Tom van Wezel2
  1. 1Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  2. 2Departments of Pathology, Leiden University Medical Center, Leiden, The Netherlands
  3. 3Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, The Netherlands
  4. 4Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  5. 5Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
  6. 6Department of Clinical Genetics, University of Maastricht, Maastricht, The Netherlands
  7. 7Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
  8. 8Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands
  9. 9Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands
  10. 10Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
  11. 11Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
  12. 12Department of Gastroenterology of the Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Frederik J Hes, Department of Clinical Genetics, Leiden University Medical Center (LUMC), PO Box 9600, K5-R, Leiden 2300 RC, The Netherlands; f.j.hes{at}lumc.nl

Abstract

Background Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20–30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas.

Methods We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs).

Results We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC.

Conclusions These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.

  • Cancer: colon
  • Clinical genetics
  • Genetic screening/counselling

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