Germline Mutations Can Promote Breast Cancer Metastasis
A new research paper was published in Oncotarget on June 30, 2022, entitled, “Role of germline variants in the metastasis of breast carcinomas.”
Most cancer-related deaths in breast cancer patients are associated with metastasis, a multistep, intricate process that requires the cooperation of tumor cells, tumor microenvironment and metastasis target tissues. It is accepted that metastasis does not depend on the tumor 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 study, a team of researchers—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—from Hospital Universitario Virgen de la Victoria de Málaga, Universidad de Málaga, CIBERONC-ISCIII, Hospital Costa del Sol, Universidad Complutense, Hospital Virgen del Rocío, Complejo Hospitalario Reina Sofía, Complejo Hospitalario de Jaén, IdISSC, Spanish National Cancer Research Centre (CNIO), Hospital Clínico Universitario, and Universidad de Valencia analyzed the host factors (i.e., germline variants) that contribute to the susceptibility to metastasis in breast cancer patients. They leveraged the extreme discordant phenotypes approach and the epistasis networks to analyze the genotypes of 97 breast cancer patients.
“We performed an epistasis network analysis to detect the variants that take part in metastasis by modulating the effect of other variants. We selected the genes that harbour these germline variants based on their role in the regulation of metastasis. We found several gene candidates through which the host’s genetic makeup contributes to metastasis.”
The researchers 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.
“In conclusion, our work moves onward with the seed and soil hypothesis—i.e., the host’s genetic background contributes to the development of metastasis. We unveiled several genes altered by germline variants that influence metastasis through their synergistic interaction with many other genes in our epistasis network. Therefore, we suggest that women who harbour specific sequence variants in the metastasis influence genes will deploy gene expression patterns that favour metastasis should they develop breast cancer.”
Reference: Santonja Á, Moya-García AA, Ribelles N, et al. Role of germline variants in the metastasis of breast carcinomas. Oncotarget. 2022;13:843-862. doi: 10.18632/oncotarget.28250
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