Familial Cancer

, Volume 15, Issue 2, pp 281–288 | Cite as

Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis

  • Isabel Spier
  • Martin Kerick
  • Dmitriy Drichel
  • Sukanya Horpaopan
  • Janine Altmüller
  • Andreas Laner
  • Stefanie Holzapfel
  • Sophia Peters
  • Ronja Adam
  • Bixiao Zhao
  • Tim Becker
  • Richard P. Lifton
  • Elke Holinski-Feder
  • Sven Perner
  • Holger Thiele
  • Markus M. Nöthen
  • Per Hoffmann
  • Bernd Timmermann
  • Michal R. Schweiger
  • Stefan Aretz
Original Article

Abstract

In up to 30 % of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.

Keywords

Familial colorectal cancer Adenomatous polyposis Candidate genes Exome sequencing Massive parallel sequencing Hereditary tumor syndromes 

Supplementary material

10689_2016_9870_MOESM1_ESM.docx (212 kb)
Supplementary material 1 (DOCX 212 kb)

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Copyright information

© Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • Isabel Spier
    • 1
    • 2
  • Martin Kerick
    • 3
    • 4
  • Dmitriy Drichel
    • 5
  • Sukanya Horpaopan
    • 1
    • 6
  • Janine Altmüller
    • 4
    • 7
  • Andreas Laner
    • 8
    • 9
  • Stefanie Holzapfel
    • 1
    • 2
  • Sophia Peters
    • 1
  • Ronja Adam
    • 1
    • 2
  • Bixiao Zhao
    • 10
  • Tim Becker
    • 5
    • 11
  • Richard P. Lifton
    • 10
  • Elke Holinski-Feder
    • 8
    • 9
  • Sven Perner
    • 12
    • 13
  • Holger Thiele
    • 4
  • Markus M. Nöthen
    • 1
    • 14
  • Per Hoffmann
    • 1
    • 14
    • 15
    • 16
  • Bernd Timmermann
    • 17
  • Michal R. Schweiger
    • 3
    • 4
  • Stefan Aretz
    • 1
    • 2
  1. 1.Institute of Human GeneticsUniversity of BonnBonnGermany
  2. 2.Center for Hereditary Tumor SyndromesUniversity of BonnBonnGermany
  3. 3.Department of Vertebrate GenomicsMax Planck Institute for Molecular GeneticsBerlinGermany
  4. 4.Cologne Center for Genomics (CCG)University of CologneCologneGermany
  5. 5.German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  6. 6.Department of Anatomy, Faculty of Medical ScienceNaresuan UniversityPhitsanulokThailand
  7. 7.Institute of Human GeneticsUniversity of CologneCologneGermany
  8. 8.Medizinische Klinik und Poliklinik IV, Campus InnenstadtKlinikum der Universität MünchenMunichGermany
  9. 9.Medizinisch Genetisches ZentrumMunichGermany
  10. 10.Departments of Genetics, Howard Hughes Medical InstituteYale University School of MedicineNew HavenUSA
  11. 11.Institute of Medical Biometry, Informatics, and EpidemiologyUniversity of BonnBonnGermany
  12. 12.Section for Prostate Cancer Research, Center for Integrated Oncology Cologne/Bonn, Institute of PathologyUniversity Hospital of BonnBonnGermany
  13. 13.Pathology Network of the University Hospital of Luebeck and Leibniz Research Center BorstelBorstelGermany
  14. 14.Department of Genomics, Life and Brain CenterUniversity of BonnBonnGermany
  15. 15.Division of Medical GeneticsUniversity Hospital BaselBaselSwitzerland
  16. 16.Department of BiomedicineUniversity of BaselBaselSwitzerland
  17. 17.Next Generation Sequencing GroupMax Planck Institute for Molecular GeneticsBerlinGermany

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