CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis.
ABSTRACT 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.
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.
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.
This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.
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ABSTRACT: Mutations of the BRCA1 gene in tumor DNA from patients with sporadic breast cancer have not yet been observed. Nevertheless, BRCA1 activity is markedly decreased in invasive breast tumors. Previous reports have shown that hypermethylation of the promoter region is an alternative mechanism to mutation for the inactivation of tumor suppressor genes. We examined the BRCA1 promoter region for hypermethylation by Southern blotting. Hypermethylation was observed in two of seven sporadic breast carcinomas but not in any normal tissues. The hypermethylation was not an artifact because a control region was unmethylated in the two tumors. Although not all tumors were hypermethylated, these observations are consistent with an important role for epigenetic mechanisms in human cancer.Cancer Research 09/1997; 57(16):3347-50. · 7.86 Impact Factor