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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy, Fine-Needle
  • Breast Neoplasms / genetics*
  • Chi-Square Distribution
  • CpG Islands / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cytokines / genetics
  • DNA Methylation
  • Female
  • Genes, BRCA1
  • Genes, BRCA2
  • Genes, Tumor Suppressor
  • Humans
  • Mutation
  • Polymerase Chain Reaction
  • Premenopause
  • Promoter Regions, Genetic / genetics
  • Receptors, Progesterone / genetics
  • Receptors, Retinoic Acid / genetics
  • Risk
  • Risk Assessment
  • Statistics, Nonparametric
  • Tumor Suppressor Proteins / genetics

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Cytokines
  • Receptors, Progesterone
  • Receptors, Retinoic Acid
  • SCGB3A1 protein, human
  • Tumor Suppressor Proteins
  • progesterone receptor B
  • retinoic acid receptor beta