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A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer

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Abstract

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.

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Acknowledgments

We are sincerely grateful to all patients participating in this study who were recruited as part of the EPICOLON project (supplementary note). We acknowledge the Spanish National DNA Bank (BNADN) for the availability of the samples. This work was supported by grants from the Fondo de Investigacion Sanitaria/FEDER (08/1276, 08/0024, PS09/02368, 11/00219, 11/00681), Instituto de Salud Carlos III (Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Ciencia e Innovación (SAF 07-64873 and SAF 2010-19273), Fundación Privada Olga Torres (CRP), Asociación Española contra el Cáncer (Fundación Científica y Junta de Barcelona), FP7 CHIBCHA Consortium (ACar, SCB and LCC), and by COST office through COST action BM1206. SCB and CFR are supported by contracts from the Fondo de Investigación Sanitaria (CP 03-0070 to SCB and PS09/02368 to CFR). LALF was supported by Miguel Servet contract from Fondo de Investigación Sanitaria (CP06/0267 and PI12/00056) and grants from Fundación Mutua Madrileña and Fundación Ramón Areces. J-BC was funded by the Wellcome Trust Core Award 075491/Z/04.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

  1. Fundación Pública Galega de Medicina Xenómica (FPGMX)-SERGAS, Grupo de Medicina Xenómica, IDIS, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer), Complexo Hospitalario Universitario de Santiago, Choupana s/n, 15706, Santiago, Spain

    C. Fernandez-Rozadilla, A. Carracedo & C. Ruiz-Ponte

  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    C. Fernandez-Rozadilla & I. Tomlinson

  3. Bioinformatics Core Group, Department of Oncology, University of Oxford, Oxford, UK

    J. B. Cazier

  4. NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK

    I. Tomlinson

  5. Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERer)-Universidad de Santiago de Compostela, 15706, Santiago, Spain

    A. Brea-Fernández

  6. Oncology Pharmacy Unit, Complejo Hospitalario Universitario of Santiago (CHUS), 15706, Santiago, Spain

    M. J. Lamas

  7. Genetics Department, Hospital de Santa Creu I Sant Pau, 08025, Barcelona, Spain

    M. Baiget

  8. Pharmacogenetics and Pharmacogenomics Laboratory, Servicio de Farmacia, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007, Madrid, Spain

    L. A. López-Fernández

  9. Gastroenterology Department, Hospital do Meixoeiro, 36214, Vigo, Spain

    J. Clofent & L. de Castro

  10. Section of Digestive Diseases, Internal Medicine Department, Hospital Sagunto, 46520, Valencia, Spain

    J. Clofent

  11. Colorectal Cancer Multidisciplinary Unit, Donostia Hospital, University of the Basque Country, San Sebastián, Spain

    L. Bujanda

  12. Servicio de Patologia Digestiva, Hospital Sant PAu, Barcelona, 08003, Spain

    D. Gonzalez

  13. Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany

    K. Hemminki

  14. Center for Primary Health Care Research, Lund University, Malmö, Sweden

    K. Hemminki

  15. Gastroenterology Department, Hospital del Mar, Barcelona, Spain

    X. Bessa & M. Andreu

  16. Gastroenterology Department, Hospital General de Alicante, Alicante, Spain

    R. Jover

  17. Section of Digestive Diseases and Nutrition, University of Illinois at Chicago, Chicago, IL, USA

    R. Xicola & X. Llor

  18. Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Centre (IDIBELL), CIBERESP, Barcelona, 08907, Spain

    V. Moreno

  19. Department of Gastroenterology, Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain

    A. Castells & S. Castellví-Bel

  20. Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jidda, Saudi Arabia

    A. Carracedo

Authors
  1. C. Fernandez-Rozadilla
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  2. J. B. Cazier
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  3. I. Tomlinson
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  4. A. Brea-Fernández
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  5. M. J. Lamas
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  6. M. Baiget
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  7. L. A. López-Fernández
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  8. J. Clofent
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  9. L. Bujanda
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  10. D. Gonzalez
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  11. L. de Castro
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  12. K. Hemminki
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  13. X. Bessa
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  14. M. Andreu
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  15. R. Jover
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  16. R. Xicola
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  17. X. Llor
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  18. V. Moreno
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  19. A. Castells
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  20. S. Castellví-Bel
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  21. A. Carracedo
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  22. C. Ruiz-Ponte
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Consortia

The EPICOLON Consortium

Corresponding author

Correspondence to C. Ruiz-Ponte.

Additional information

The EPICOLON consortium for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.

Electronic supplementary material

Below is the link to the electronic supplementary material.

439_2013_1390_MOESM1_ESM.pptx

Supplementary Figure 1. Distribution of CNVRs by chromosome. Frequencies for each CNVR are shown comparing Birdseye (green) and QuantiSNP (blue) locations in the controls; CNVRs with frequencies over 5% are CNPs; from left to right and top to bottom: chromosomes 1 to 10 (PPTX 5511 kb)

Supplementary Figure 1. (Continuation). From left to right and top to bottom: chromosomes 11 to 22 (PPTX 4597 kb)

Supplementary note: Members of EPICOLON consortium (PDF 66 kb)

439_2013_1390_MOESM4_ESM.docx

Supplementary Table 1: Overlapping CNPs between Birdseye and QuantiSNP. Features for the 56 CNPs that are shared between algorithms (DOCX 132 kb)

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Fernandez-Rozadilla, C., Cazier, J.B., Tomlinson, I. et al. A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer. Hum Genet 133, 525–534 (2014). https://doi.org/10.1007/s00439-013-1390-4

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  • DOI: https://doi.org/10.1007/s00439-013-1390-4

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