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Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):901-14. doi: 10.1158/1055-9965.EPI-08-0875. Epub 2009 Mar 3.

CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis.

Author information

1
Department of Medicine, Duke University Medical Center, Box 2628, Durham, NC 27710, USA.

Abstract

BACKGROUND:

Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known.

METHODS:

CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1.

RESULTS:

Although the overall frequency of CpG island promoter methylation events increased with age (P<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had <or=4 methylation events), whereas women without a mutation showed a high frequency of promoter methylation events (24 of 25 women had 5-8 methylation events; P<0.0001). Of women with a BRCA1/2 mutation, none showed methylation of HIN-1 and only 1 of 15 women showed CpG island methylation of RARB M4, INK4a/ARF, or PRB promoters.

CONCLUSIONS:

This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.

PMID:
19258476
PMCID:
PMC2667866
DOI:
10.1158/1055-9965.EPI-08-0875
[Indexed for MEDLINE]
Free PMC Article

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