Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer.
BACKGROUND
Promoter methylation is a common epigenetic mechanism to silence tumor suppressor genes during breast cancer development. We investigated whether BRCA1-associated breast tumors show cancer-predictive methylation patterns similar to those found in sporadic tumors.


METHODS
Quantitative multiplex methylation-specific PCR of 11 genes involved in breast carcinogenesis (RARB, RASSF1, TWIST1, CCND2, ESR1, SCGB3A1, BRCA1, BRCA2, CDKN2A, APC, CDH1) was carried out on 32 BRCA1-associated and 46 sporadic breast carcinomas and on normal breast tissue from seven BRCA1 mutation carriers and 13 non-carriers.


RESULTS
The extent of cumulative methylation increased with age (P < 0.001). The median cumulative methylation index (CMI) of all studied genes was significantly higher in tumors (89) than in normal tissue (13, P < 0.001). The median CMI was significantly lower in BRCA1-associated (59) than in sporadic breast tumors (122, P = 0.001), in estrogen receptor (ER)-negative tumors (73) than in ER-positive tumors (122, P = 0.005) and in lymph node-negative (77) compared with lymph node-positive tumors (137, P = 0.007). In subgroup analysis, the effect of a BRCA1 germline mutation on methylation proved to be independent of ER status, lymph node status and age.


CONCLUSIONS
These data indicate that BRCA1-associated breast cancers show less promoter methylation compared with sporadic breast carcinomas indicating a difference in disease etiology.
Suijkerbuijk
K P M
KP
Department of Pathology, University Medical Center Utrecht, The Netherlands.
Fackler
M J
MJ
Sukumar
S
S
van Gils
C H
CH
van Laar
T
T
van der Wall
E
E
Vooijs
M
M
van Diest
P J
PJ
D000328:Adult; D000367:Age Factors; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D005819:Genetic Markers; D018095:Germ-Line Mutation; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics
D004273:DNA, Neoplasm; D005819:Genetic Markers; D011960:Receptors, Estrogen