Τίτλος:
Circulating cell-free DNA in breast cancer: size profiling, levels, and methylation patterns lead to prognostic and predictive classifiers
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Blood circulating cell-free DNA (ccfDNA) is a suggested biosource of valuable clinical information for cancer, meeting the need for a minimally-invasive advancement in the route of precision medicine. In this paper, we evaluated the prognostic and predictive potential of ccfDNA parameters in early and advanced breast cancer. Groups consisted of 150 and 16 breast cancer patients under adjuvant and neoadjuvant therapy respectively, 34 patients with metastatic disease and 35 healthy volunteers. Direct quantification of ccfDNA in plasma revealed elevated concentrations correlated to the incidence of death, shorter PFS, and non-response to pharmacotherapy in the metastatic but not in the other groups. The methylation status of a panel of cancer-related genes chosen based on previous expression and epigenetic data (KLK10, SOX17, WNT5A, MSH2, GATA3) was assessed by quantitative methylation-specific PCR. All but the GATA3 gene was more frequently methylated in all the patient groups than in healthy individuals (all p < 0.05). The methylation of WNT5A was statistically significantly correlated to greater tumor size and poor prognosis characteristics and in advanced stage disease with shorter OS. In the metastatic group, also SOX17 methylation was significantly correlated to the incidence of death, shorter PFS, and OS. KLK10 methylation was significantly correlated to unfavorable clinicopathological characteristics and relapse, whereas in the adjuvant group to shorter DFI. Methylation of at least 3 or 4 genes was significantly correlated to shorter OS and no pharmacotherapy response, respectively. Classification analysis by a fully automated, machine learning software produced a single-parametric linear model using ccfDNA plasma concentration values, with great discriminating power to predict response to chemotherapy (AUC 0.803, 95% CI [0.606, 1.000]) in the metastatic group. Two more multi-parametric signatures were produced for the metastatic group, predicting survival and disease outcome. Finally, a multiple logistic regression model was constructed, discriminating between patient groups and healthy individuals. Overall, ccfDNA emerged as a highly potent predictive classifier in metastatic breast cancer. Upon prospective clinical evaluation, all the signatures produced could aid accurate prognosis. © 2019, Springer Nature Limited.
Συγγραφείς:
Panagopoulou, M.
Karaglani, M.
Balgkouranidou, I.
Biziota, E.
Koukaki, T.
Karamitrousis, E.
Nena, E.
Tsamardinos, I.
Kolios, G.
Lianidou, E.
Kakolyris, S.
Chatzaki, E.
Εκδότης:
Nature Publishing Group
Λέξεις-κλειδιά:
antineoplastic agent; circulating cell free DNA; DNA; DNA mismatch repair protein MSH2; transcription factor GATA 3; transcription factor Sox17; unclassified drug; Wnt5a protein; cell free nucleic acid; DNA; kallikrein; tumor marker, adjuvant therapy; adult; Article; automation; blood level; breast cancer; cancer adjuvant therapy; cancer mortality; cancer patient; cancer prognosis; cancer recurrence; cancer size; cancer staging; cancer survival; classifier; clinical article; clinical feature; clinical outcome; controlled study; diagnostic test accuracy study; DNA blood level; DNA determination; DNA methylation; epigenetics; female; GATA3 gene; gene; gene expression; genetic parameters; histopathology; human; incidence; KLK10 gene; machine learning; metastasis potential; MSH2 gene; overall survival; polymerase chain reaction; predictive value; priority journal; progression free survival; quantitative analysis; receiver operating characteristic; reference value; sensitivity and specificity; SOX17 gene; treatment response; WNT5A gene; aged; blood; breast; breast tumor; DNA methylation; genetic epigenesis; metabolism; middle aged; pathology; physiology; prognosis; very elderly, Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Breast; Breast Neoplasms; Cell-Free Nucleic Acids; DNA Methylation; DNA, Neoplasm; Epigenesis, Genetic; Female; Humans; Kallikreins; Middle Aged; Prognosis
DOI:
10.1038/s41388-018-0660-y
