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Candidate predisposing germline copy number variants in early onset colorectal cancer patients

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Abstract

Purpose

A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset.

Methods/patients

We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter.

Results

We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis.

Conclusions

These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

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Acknowledgements

This work was supported by grants from the Fondo de Investigación Sanitaria/FEDER (11/00681, 11/00219), and COST Action BM1206 (EUCOLONGENE). AJB-F is supported by a contract from CIBERER (Centro de Investigacion Biomedica en Red de Enfermedades Raras). CIBERER is funded by the Instituto de Salud Carlos III. We are sincerely grateful to the patients who generously contributed to this study.

Author information

Authors and Affiliations

  1. Grupo de Medicina Xenomica-USC, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain

    A. J. Brea-Fernandez & A. Carracedo

  2. Fundacion Publica Galega de Medicina Xenomica (FPGMX)-SERGAS, Grupo de Medicina Xenomica, Hospital Clínico Universitario, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), IDIS, Edificio de Consultas, planta-2, Choupana s/n, 15706, Santiago de Compostela, Spain

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

  3. Grupo de Medicina Xenomica-USC, Santiago de Compostela, Spain

    M. Alvarez-Barona & A. Carracedo

  4. Translational Research Laboratory, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, Spain

    D. Azuara, M. M. Ginesta & G. Capella

  5. Gastroenterology Department, Hospital do Meixoeiro, Vigo, Spain

    J. Clofent & L. de Castro

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

    J. Clofent

  7. Servicio de Patologia Digestiva, Hospital Sant Pau, Barcelona, Spain

    D. Gonzalez

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

    M. Andreu & X. Bessa

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

    X. Llor & R. Xicola

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

    R. Jover

  11. Department of Gastroenterology, Hospital Clinic, Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain

    A. Castells & S. Castellvi-Bel

Authors
  1. A. J. Brea-Fernandez
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  2. C. Fernandez-Rozadilla
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  3. M. Alvarez-Barona
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  4. D. Azuara
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  7. L. de Castro
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  8. D. Gonzalez
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  9. M. Andreu
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  10. X. Bessa
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  11. X. Llor
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  12. R. Xicola
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  13. R. Jover
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  15. S. Castellvi-Bel
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  16. G. Capella
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  17. A. Carracedo
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  18. C. Ruiz-Ponte
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Corresponding author

Correspondence to C. Ruiz-Ponte.

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The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Brea-Fernandez, A.J., Fernandez-Rozadilla, C., Alvarez-Barona, M. et al. Candidate predisposing germline copy number variants in early onset colorectal cancer patients. Clin Transl Oncol 19, 625–632 (2017). https://doi.org/10.1007/s12094-016-1576-z

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  • DOI: https://doi.org/10.1007/s12094-016-1576-z

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