Intratumor heterogeneity index of breast carcinomas based on DNA methylation profiles

Autor: María Roqué, Emanuel M. Campoy, Luis S. Mayorga, Maria Teresita Branham
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Datasets as Topic
Estrogen receptor
Apoptosis
Epigenesis
Genetic
purl.org/becyt/ford/1 [https]
0302 clinical medicine
Cell Movement
Surgical oncology
Prognosis and predictive factors
PROMOTER METHYLATION
Breast
Intratumor heterogeneity - promoter methylation
Promoter Regions
Genetic
medicine.diagnostic_test
Carcinoma
Ductal
Breast
Methylation
Bioquímica y Biología Molecular
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
TCGA - heterogeneity index - breast Cancer - cellular clones
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
DNA methylation
Female
CIENCIAS NATURALES Y EXACTAS
Research Article
Adult
Breast Neoplasms
Biology
lcsh:RC254-282
Flow cytometry
Ciencias Biológicas
03 medical and health sciences
BREAST CANCER
Cell Line
Tumor
Genetics
medicine
Humans
Epigenetics
Allele
purl.org/becyt/ford/1.6 [https]
Cell Proliferation
DNA Methylation
TCGA
030104 developmental biology
INTRATUMOR HETEROGENEITY
CELLULAR CLONES
Cancer cell
Cancer research
PROGNOSIS AND PREDICTIVE FACTORS
CpG Islands
HETEROGENEITY INDEX
Zdroj: BMC Cancer, Vol 19, Iss 1, Pp 1-15 (2019)
CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
BMC Cancer
ISSN: 1471-2407
DOI: 10.1186/s12885-019-5550-3
Popis: Background: Cancer 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. Methods: DNA extracted from different tumor cell populations (breast carcinomas, cancer cell lines and cellular 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. Cellular clones were obtained from single cells derived of MDA-MB 231 cancer cell lines applying serial limiting dilution method and morphology was analyzed by optical microscopy and flow cytometry. Clones characteristics were examined through cellular proliferation, migration capacity and apoptosis. Heterogeneity index was also calculated from beta values derived from methylation profiles of TCGA tumors. Results: The 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 developed an 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 clones obtained from the MDA-MB 231 cancer cell line generated their own new heterogeneity over time. Using 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 < 0.0001) and HER2 positivity (p = 0.0007). When we analyzed molecular subtypes we found that they presented different heterogeneity levels. Interestingly, we also observed that all mentioned tumor cell populations shared a similar Heterogeneity index (HI) mean. Conclusions: Our results show that each tumor presents a unique epigenetic heterogeneity level, which is associated with prognostic and predictive factors. We also observe that breast tumor subtypes differ in terms of epigenetic heterogeneity, which could serve as a new contribution to understand the different prognosis of these groups. Fil: Campoy, Emanuel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina Fil: Branham, Maria Teresita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina Fil: Mayorga, Luis Segundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina Fil: Roque Moreno, Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentina
Databáze: OpenAIRE
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