Biomarcadores circulantes em mulheres com lesões impalpáveis da mama

• Autor(a) principal: Silva, Lucas Delmonico Rodrigues da
• Data de Publicação: 2019
• Outros Autores: [e-mail]
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/19949
• topic: Impalpable breast lesions; Early detection; TP53; CDKN2A; PIK3CA; ATM; Lesões mamárias impalpáveis; Detecção precoce; TP53; CDKN2A; PIK3CA; ATM; CIENCIAS DA SAUDE::MEDICINA

Breast cancer is the leading cancer death cause in the world for women. In this context, the breast early detection increases the cure chances greatly, however the initial characterization of the impalpable lesions has become a challenge. Histologically, these lesions contain in situ and infiltrative cells, which makes it difficult to predict their potential for evolution. The search for circulating tumor biomarkers has been extensively explored in an attempt to minimize invasive, repetitive procedures and aggressive treatments in these cases. The aim of this study was to detect circulating biomarkers involved in the development of impalpable breast lesion with classification BIRADS-3 and 4. For this purpose: the methylation profile of CDKN2A (p14ARF and p16INK4A) and ATM promoters; the detection of somatic mutations in TP53 (exon 4 to 9), CDKN2A (exons 1 to 3), PIK3CA (exons 9 and 20) genes in tumor and circulating free DNA; and the identification of proteins differentially expressed in the saliva and plasma from patients with impalpable breast lesions were performed. Together, these results generated five publications. Briefly, two cohorts (N=62 and N=56) were evaluated for the methylation detection in the promoters of CDKN2A (p14ARF and p16INK4A), and ATM. For the two cohorts, methylation frequencies in blood DNA were 41%-37.5%, 26%-27%, and 41%-48% for the ATM, p14ARF and p16INK4a genes, respectively. The methylation frequency found in tumors (N=62) was 1/62 (1.6%), 3/62 (4.8%) and 33/62 (53.2%) for p14ARF and p16INK4a and ATM, respectively. Regarding the mutational evaluation, the PIK3CA, TP53 and CDKN2A genes were sequenced (PCR-Sanger) in 58 women with impalpable lesions (49 malignant and 9 benign) with their respective free circulating DNA. A total of 37 mutations were found, being 8/58 (14%), 18/58 (31%) and 11/58 (19%) for the PIK3CA, TP53 and CDKN2A genes, respectively. Regarding the proteomic data the main proteins differentially expressed in the saliva from the patients compared to the controls were: α2-macroglobulin, ceruloplasmin, leukocyte elastase inhibitor, α-enolase, and deleted in malignant brain tumors 1. In relation to plasma, alpha -2-macroglobulin and ceruplasmin are in high expression, whereas other proteins such as haptoglobin, hemopexin and vitamin D binding protein were in low expression compared to the control. Based on these results, we measured plasma vitamin D in 65 patients with impalpable breast lesions and in 20 controls. The prevalence of vitamin D deficiency and/or insufficiency in women with malignant lesions and in the controls were 84% and 60%, respectively. In this study the results are unpublished, however the biomarkers candidates described here need further investigation to describe and validate their involvement in the development of impalpable breast lesions.