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Research Paper

Quantitative detection of methylated ESR1 and 14-3-3-σ gene promoters in serum as candidate biomarkers for diagnosis of breast cancer and evaluation of treatment efficacy

Joaquina Martínez-Galán, Blanca Torres, Rosario del Moral, José Antonio Muñoz-Gámez, David Martín-Oliva, Mercedes Villalobos, María Isabel Núñez, Juan de Dios Luna, Francisco Javier Oliver and José Mariano Ruiz de Almodóvar,

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The aim of the present study was to investigate the association between gene hypermethylation and main clinicopathological features of breast cancer, including diagnosis and treatment response. A sensitive SYBR green methylation-specific PCR technique was used to analyze the utility of circulating DNA with CpG island hypermethylation of ESR1, APC, RARB, 14-3-3-σ, and E-cad gene promoter regions as breast cancer biomarkers. Analyses were conducted of preoperative sera from 106 women with breast cancer, 34 with benign breast disease and 74 with no evidence of breast disease and of post-treatment sera from 60 of the breast cancer patients. Mean serum values of methylated ESR1 and 14-3-3-σ gene promoters significantly differed between breast cancer patients and healthy controls (P = 0.0112 for ESR1 and P = 0.0047 for 14-3-3-σ). When their results were combined, it was found that hypermethylation of these two genes differentiated between breast cancer patients and healthy controls (P < 0.0001) with a sensitivity of 81% (95% confidence interval: 72-88%) and specificity of 88% (95% CI: 78-94%). Presence of methylated ESR1 in serum of breast cancer patients was associated with the ER negative phenotype (P = 0.0179). Serum hypermethylation at ESR1 and 14-3-3-σ loci was observed in cancer patients, in situ carcinoma and benign breast disease. No significant differences in methylated ERS1 or 14-3-3-σ values were observed between pre-surgery and post-treatment measurements. Preliminary clinical applications of this approach have revealed several shortcomings, including a frequent presence of methylated 14-3-3-σ in sera from women with breast benign disease. These findings cast some doubts on the utility for early cancer diagnosis of highly sensitive techniques to identify hypermethylation of specific gene promoters in DNA extracted from serum. Although numerous issues remain to be resolved, the quantitative measurement of circulating methylated DNA remains a promising tool for cancer risk assessment.

Authors

Joaquina Martínez-Galán

Servicio de Oncología Radioterápica. Hospital Virgen de las Nieves. Granada, Spain

Blanca Torres

CIBER de Epidemiología y Salud Pública

Rosario del Moral

Servicio de Oncología Radioterápica. Hospital Virgen de las Nieves. Granada, Spain

José Antonio Muñoz-Gámez

Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Spain

David Martín-Oliva

Departamento de Biología Celular; Universidad de Granada; Granada, Spain

Mercedes Villalobos

Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Spain

María Isabel Núñez

Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Spain

Juan de Dios Luna

Departamento de Bioestadística, Universidad de Granada, Spain

Francisco Javier Oliver

Instituto de Parasitología y Biomedicina, CSIC, Granada, Spain

José Mariano Ruiz de Almodóvar,

Instituto de Biopatología y Medicina Regenerativa, Centro de Investigación Biomédica, Universidad de Granada, Spain

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.