Genetics and epigenetics

Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis




Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation.


The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC.


Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI ≤ 25 kg/m2) or overweight/obese (BMI > 25 kg/m2). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples.


The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified genes were involved in inflammatory and metabolic functional processes. Among these genes, novel genes were identified as epigenetically regulated in CRC depending on adiposity. ZNF397OS and ZNF543 represented the top scoring associated events that were further validated in an independent cohort and exhibited strong correlation with BMI and excellent and statistically significant efficiency in the discrimination of obese from non-obese CRC patients (area under the curve >0.80; p < 0.05).


The present study identifies a potential epigenome mark of obesity-related CRC that could be useful for precision medicine in the management of this disease taking into account adiposity as a relevant risk factor.

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We thank María Amil, Diana García, and Carles Arribas for their technical support, as well as Biobank of the Public Health System of Andalusia (BBSSPA) of the health counseling and the head of the Anatomical Pathology Department of the Hospital Complex of Specialties Virgen de la Victoria Malaga Spain.


This study was supported by “Centros de Investigacion Biomedica En Red” (CIBERobn) of the “Instituto de Salud Carlos III” (ISCIII), and grants from ISCIII (PI11/01661, PI14/01012, PI15/01114, PE13/00024) co-financed by the European Regional Development Fund (FEDER). DC-C was recipient of an FPU grant from Education Ministry, Madrid, Spain (13/04211). AD-L was funded by the ISCIII through a research contract "Rio Hortega" (CM14/00067) and "Juan Rodés" (JR17/00016), ABC and JS are “Miguel Servet” researchers (ISCIII, CP17/00088 and CP13/00055, respectively) and MM-G was recipient of the Nicolas Monarde program from the Servicio Andaluz de Salud, Junta de Andalucia, Spain (C-0029-2014).

Author information

Author notes

  1. These authors contributed equally: Manuel Macias-Gonzalez, Felipe F. Casanueva, Francisco J. Tinahones.


  1. Laboratory of Molecular and Cellular Endocrinology, Instituto de Investigacion Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela University (USC), Santiago de Compostela, Spain

    • Ana B. Crujeiras
    •  & Felipe F. Casanueva
  2. CIBERobn Fisiopatologia de la Nutricion y Obesidad (CB06/03), Madrid, Spain

    • Ana B. Crujeiras
    • , Sonsoles Morcillo
    • , Daniel Castellano-Castillo
    • , Manuel Macias-Gonzalez
    • , Felipe F. Casanueva
    •  & Francisco J. Tinahones
  3. Unidad de Gestion Clinica Endocrinologia y Nutricion, Instituto de Investigacion Biomédica de Malaga (IBIMA), Complejo Hospitalario de Malaga (Virgen de la Victoria), Universidad de Malaga, Malaga, Spain

    • Sonsoles Morcillo
    • , Daniel Castellano-Castillo
    • , Manuel Macias-Gonzalez
    •  & Francisco J. Tinahones
  4. Translational Medical Oncology (Oncomet), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), CIBERONC, Santiago de Compostela, Spain

    • Angel Diaz-Lagares
  5. Laboratory of Personalized Medicine, Epigenomics Unit, Medical Research Institute La Fe, Valencia, Spain

    • Juan Sandoval
  6. Unidad de Gestion Clinica de Oncologia Integral. Complejo Hospitalario de Malaga (Virgen de la Victoria), Servicio Andaluz de Salud, Malaga, Spain

    • Esperanza Torres
  7. Biostatistics Unit, Medical Research Institute La Fe, Valencia, Spain

    • David Hervas
  8. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, Barcelona, Spain

    • Sebastian Moran
    •  & Manel Esteller
  9. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain

    • Manel Esteller


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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Ana B. Crujeiras or Manuel Macias-Gonzalez.

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