Intratumor heterogeneity index of breast carcinomas based on DNA methyla􀆟on profiles

BRANHAM, MARÍA T.; MAYORGA, LUIS; CAMPOY, EMANUEL MARTIN; ROQUÉ, MARÍA

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la SAIC; 2018

Sociedad Argentina de Investigación Clínica

BackgroundCancer cells evolve and constitute heterogeneous populations that fluctuate in space and time and are subjected to selection generating intratumor heterogeneity. This phenomenon is determined by the acquisition of genetic/epigenetic alterations and their selection over time which has clinical implications on drug resistance.MethodsDNA extracted from different tumor cell populations (breast carcinomas, cancer cell lines and cellular sub-clones) were analyzed by MS-MLPA. Methylation profiles were used to generate a heterogeneity index to quantify the magnitude of epigenetic heterogeneity in these populations. ResultsThe study of methylation profiles of 23 fresh breast carcinomas revealed heterogeneous allele populations in these tumor pieces. With the purpose to measure the magnitude of epigenetic heterogeneity, we develop a heterogeneity index based on methylation information and observed that all tumors present their own heterogeneity level. Applying the index calculation in pure cancer cell populations such as cancer cell lines (MDA-MB 231, MCF-7, T47D, HeLa and K-562), we also observed epigenetic heterogeneity. In addition, we detected that sub-clones obtained from MDA-MB 231 cancer cell line diverged from the initial population over time and generated their own new heterogeneity without selective pressure. Using epigenetic information derived from TCGA tumors, we determined that the heterogeneity index correlated with prognostic and predictive factors like tumor size (p=0.0088), number of affected axillary nodes (p=0.007), estrogen receptor expression (p