CHANGES IN CpG ISLANDS METHYLATION PATTERNS DURING DUCTAL BREAST CARCINOMA PROGRESSION

• Published in: Cancer epidemiology, biomarkers & prevention Vol. 18; no. 10; pp. 2694 - 2700
• Main Authors: Hoque, Mohammad Obaidul, Prencipe, Maria, Poeta, Maria Luana, Valori, Vanna Maria, Gallo, Antonietta Pia, Ostrow, Kimberly, Bonghi, Loriana, Vitale, Rita, Maiello, Evaristo, Apicella, Adolfo, Rossiello, Raffaele, Zito, Francesco, Stefania, Tommasi, Paradiso, Angelo, Schittulli, Francesco, Carella, Massimo, Dallapiccola, Bruno, Murgo, Roberto, Carosi, Illuminato, Bisceglia, Michele, Fazio, Vito Michele, Sidransky, David, Parrella, Paola
• Format: Journal Article
• Language: English
• Published: 29.09.2009
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.EPI-08-0821

CpG island hypermethylation is emerging as one of the main mechanisms for inactivation of cancer related genes in breast tumorigenesis. We examined the changes in methylation patterns during ductal breast cancer progression from atypical ductal hyperplasia to in situ and invasive carcinoma. Paired samples of synchronous pre invasive lesions (Atypical Ductal Hyperplasia and/or Ductal Carcinoma in situ ) and invasive ductal breast carcinoma from 31 patients, together with isolated lesions from additional 24 patients were studied. Overall, 95 pathological samples and 20 normal breast tissues were analyzed by Quantitative Methylation Specific PCR (QMSP) on a panel of 9 gene promoters ( ESR1 , APC , CDH1 , CTNNB1 , GSTPI , THBS1 , MGMT , TMS1 and TIMP3 ). APC , CDH1 , and CTNNB1 promoter regions showed an increase in frequency of methylation and increased methylation levels in pathological samples when compared with normal breast tissues. The analysis of the syncronous paired breast lesions demonstrated also an increase in methylation frequency and level for APC , CDH1 , and CTNNB1 genes during progression. By establishing a cutoff value, we were able to distinguish among -invasive and invasive lesions. Synchronous methylation of APC , CDH1 , and CTNNB1 was associated only with invasive lesions, whereas simultaneous methylation of APC and CDH1 or APC and CTNNB1 were more frequent in ductal carcinoma in situ and invasive carcinoma. Our data point to direct involvement of APC , CDH1 , and CTNNB1 CpG island promoter methylation in the early stages of breast cancer progression, and suggest that these molecular alterations might be involved in the transition to an invasive phenotype.