RESUMEN
In a series of invasive ductal breast carcinoma, we investigated the status of chromosomal and intrachromosomal instability by fluorescence in situ hybridisation and determined the level of mRNA expression for two genes involved in the mitotic spindle checkpoint pathway, BUB1B and MAD2L1. All breast cancers demonstrated higher chromosomal instability rates in tumor samples (average: 56.86%, range: 36.24-76.78%) than in controls (average: 11.54%, range: 9.91-14.84%) (P<0.0001). As well as intrachromosomal instability rates were elevated in tumor (average: 18.45% range: 8.34-35.8%) as compared with controls (average: 4.18% range: 3.47-4.81%) (P<0.0001). An increase in BUB1B and MAD2L1 transcripts was demonstrated in the majority of the tumor tested. BUB1B mRNA levels but not MAD2L1 levels correlated with intrachromosomal instability (r=0.722, P=0.018).
Asunto(s)
Neoplasias de la Mama/genética , Proteínas de Unión al Calcio/genética , Carcinoma Ductal/genética , Proteínas de Ciclo Celular/genética , Inestabilidad Cromosómica , Inestabilidad Genómica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Represoras/genética , Adulto , Anciano , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal/patología , Carcinoma Ductal/cirugía , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 8 , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Proteínas Mad2 , Persona de Mediana Edad , ARN Mensajero/genéticaRESUMEN
The HIC1 gene is a transcriptional regulator commonly methylated in a variety of human cancer. Thirty-three invasive ductal carcinomas of the breast and 21 matched normal breast tissues were analysed for HIC1 promoter methylation, and allelic loss of a 700 kb region spanning the gene locus. At least one genetic or epigenetic abnormality was found in 27 of the carcinomas tested (82%). Promoter methylation was demonstrated in 21 carcinomas (64%), and nine normal tissues (43%), whereas 18 malignant tumors (54%) showed allelic loss. Concomitant loss of heterozigosity and promoter hypermethylation in the region spanning HIC1 was detected in eight carcinomas (24%) suggesting that in this subset of tumors both copies of the gene are functionally lost. These observations support a role for the HIC1 gene in the pathogenesis of breast ductal carcinomas.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Metilación de ADN , Regiones Promotoras Genéticas , Factores de Transcripción/genética , Deleción Cromosómica , Cromosomas Humanos Par 17/genética , Análisis Mutacional de ADN , ADN de Neoplasias/análisis , Proteínas de Unión al ADN , Femenino , Humanos , Factores de Transcripción de Tipo Kruppel , Repeticiones de MicrosatéliteRESUMEN
PURPOSE: In an effort to additionally determine the global patterns of CpG island hypermethylation in sporadic breast cancer, we searched for aberrant promoter methylation at 10 gene loci in 54 primary breast cancer and 10 breast benign lesions. EXPERIMENTAL DESIGN: Genomic DNA sodium bisulfate converted from benign and malignant tissues was used as template in methyl-specific PCR for BRCA1, p16, ESR1, GSTP1, TRbeta1, RARbeta2, HIC1, APC, CCND2, and CDH1 genes. RESULTS: The majority of the breast cancer (85%) showed aberrant methylation in at least 1 of the loci tested with half of them displaying 3 or more methylated genes. The highest frequency of aberrant promoter methylation was found for HIC1 (48%) followed by ESR1 (46%), and CDH1 (39%). Similar methylation frequencies were detected for breast benign lesions with the exception of the CDH1 gene (P = 0.02). The analysis of methylation distribution indicates a statistically significant association between methylation of the ESR1 promoter, and methylation at CDH1, TRbeta1, GSTP1, and CCND2 loci (P < 0.03). Methylated status of the BRCA1 promoter was inversely correlated with methylation at the RARbeta2 locus (P < 0.03). CONCLUSIONS: Our results suggest a nonrandom distribution for promoter hypermethylation in sporadic breast cancer, with tumor subsets characterized by aberrant methylation of specific cancer-related genes. These breast cancer subgroups may represent separate biological entities with potential differences in sensitivity to therapy, occurrence of metastasis, and overall prognosis.