Research Papers:

Role of germline variants in the metastasis of breast carcinomas

Ángela Santonja, Aurelio A. Moya-García _, Nuria Ribelles, Begoña Jiménez-Rodríguez, Bella Pajares, Cristina E. Fernández-De Sousa, Elísabeth Pérez-Ruiz, María del Monte-Millán, Manuel Ruiz-Borrego, Juan de la Haba, Pedro Sánchez-Rovira, Atocha Romero, Anna González-Neira, Ana Lluch and Emilio Alba

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Oncotarget. 2022; 13:843-862. https://doi.org/10.18632/oncotarget.28250

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Ángela Santonja1,2,*, Aurelio A. Moya-García2,3,*, Nuria Ribelles4,5, Begoña Jiménez-Rodríguez4, Bella Pajares4, Cristina E. Fernández-De Sousa1,2, Elísabeth Pérez-Ruiz6, María del Monte-Millán5,7, Manuel Ruiz-Borrego8, Juan de la Haba5,9, Pedro Sánchez-Rovira10, Atocha Romero11, Anna González-Neira12, Ana Lluch5,13,14 and Emilio Alba2,4,5

1 Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Spain

2 Laboratorio de Biología Molecular del Cáncer, Centro de Investigaciones Médico-Sanitarias (CIMES), Universidad de Málaga, Málaga, Spain

3 Departmento de Biología Molecular y Bioquímica, Universidad de Málaga, Málaga, Spain

4 Unidad de Gestión Clínica Intercentro de Oncología, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Málaga, Spain

5 Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain

6 Medical Oncology Service, Hospital Costa del Sol, Marbella, Málaga, Spain

7 Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain

8 Medical Oncology Service, Hospital Virgen del Rocío, Sevilla, Spain

9 Biomedical Research Institute, Complejo Hospitalario Reina Sofía, Córdoba, Spain

10 Department of Oncology, Complejo Hospitalario de Jaén, Jaén, Spain

11 Molecular Oncology Laboratory, Hospital Clínico San Carlos, IdISSC, Madrid, Spain

12 Human Genotyping-CEGEN Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

13 Department of Oncology and Hematology, Hospital Clínico Universitario, Valencia, Spain

14 INCLIVA Biomedical Research Institute, Universidad de Valencia, Valencia, Spain

* These authors contributed equally to this work

Correspondence to:

Aurelio A. Moya-García, email: [email protected]

Keywords: breast cancer; germline variants; epistasis; network analysis; seed and soil

Received: March 04, 2022     Accepted: June 20, 2022     Published: June 30, 2022

Copyright: © 2022 Santonja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Most cancer-related deaths in breast cancer patients are associated with metastasis, a multistep, intricate process that requires the cooperation of tumour cells, tumour microenvironment and metastasis target tissues. It is accepted that metastasis does not depend on the tumour characteristics but the host’s genetic makeup. However, there has been limited success in determining the germline genetic variants that influence metastasis development, mainly because of the limitations of traditional genome-wide association studies to detect the relevant genetic polymorphisms underlying complex phenotypes. In this work, we leveraged the extreme discordant phenotypes approach and the epistasis networks to analyse the genotypes of 97 breast cancer patients. We found that the host’s genetic makeup facilitates metastases by the dysregulation of gene expression that can promote the dispersion of metastatic seeds and help establish the metastatic niche—providing a congenial soil for the metastatic seeds.

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