Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors.
OBJECTIVE
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.


METHODS
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.
Laboratory of Gene Therapy and Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. pparrella@operapadrepio.it
Paola
P
Parrella
Maria Luana
ML
Poeta
Antonietta Pia
AP
Gallo
Maria
M
Prencipe
Marina
M
Scintu
Adolfo
A
Apicella
Raffaele
R
Rossiello
Giuseppina
G
Liguoro
Davide
D
Seripa
Carolina
C
Gravina
Carla
C
Rabitti
Monica
M
Rinaldi
Theresa
T
Nicol
Stefania
S
Tommasi
Angelo
A
Paradiso
Francesco
F
Schittulli
Vittorio
V
Altomare
Vito Michele
VM
Fazio
D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015226:Dinucleoside Phosphates / Q000235:genetics; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*
D004273:DNA, Neoplasm; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide