Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression.
Aberrant promoter methylation of several known or putative tumor suppressor genes occurs frequently during carcinogenesis, and this epigenetic change has been considered as a potential molecular marker for cancer. We examined the methylation status of nine genes (APC, CDH1, CTNNB1, TIMP3, ESR1, GSTP1, MGMT, THBS1, and TMS1), by quantitative methylation specific PCR. Synchronous preinvasive lesions (atypical ductal hyperplasia and/or ductal carcinoma in situ) and invasive ductal breast carcinoma from 52 patients, together with pure lesions from 24 patients and 12 normal tissues paired to tumor and 20 normal breast distant from tumor were analyzed. Aberrant promoter methylation was detected in both preinvasive and invasive lesions for genes APC, CDH1, CTNNB1, TIMP3, ESR1, and GSTP1. However, hierarchical mixed model and Generalized Estimating Equations model analyses showed that only APC, CDH1, and CTNNB1 promoter regions showed a higher frequency and methylation levels in pathologic samples when compared with normal breast. Whereas APC and CTNNB1 did not show differences in methylation levels or frequencies, CDH1 showed higher methylation levels in invasive tumors as compared with preinvasive lesions (P < 0.04, Mann-Whitney test with permutation correction). The analysis of APC, CDH1, and CTNNB1 methylation status was able to distinguish between normal and pathologic samples with a sensitivity of 67% (95% confidence interval, 60-71%) and a specificity of 75% (95% confidence interval, 69-81%). Our data point to the direct involvement of APC, CDH1, and CTNNB1 promoter methylation in the early stages of breast cancer progression and suggest that they may represent a useful tool for the detection of tumor cells in clinical specimens.
Department of Otolaryngology Head and Neck Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Mohammad Obaidul
MO
Hoque
Maria
M
Prencipe
Maria Luana
ML
Poeta
Raffaela
R
Barbano
Vanna Maria
VM
Valori
Massimiliano
M
Copetti
Antonietta Pia
AP
Gallo
Mariana
M
Brait
Evaristo
E
Maiello
Adolfo
A
Apicella
Raffaele
R
Rossiello
Francesco
F
Zito
Tommasi
T
Stefania
Angelo
A
Paradiso
Massimo
M
Carella
Bruno
B
Dallapiccola
Roberto
R
Murgo
Illuminato
I
Carosi
Michele
M
Bisceglia
Vito Michele
VM
Fazio
David
D
Sidransky
Paola
P
Parrella
D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic