CpG Island Tumor Suppressor Promoter Methylation in Non-BRCA-Associated Early Mammary Carcinogenesis

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 ≤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.

Effects of preoperative and postoperative enteral nutrition on postoperative nutritional status and immune function of gastric cancer patients

“…No serious organ damages and metabolism and endocrine diseases were diagnosed in the preoperative examinations of patients. Tumor staging, operative methods and operative time of the patients in the two groups did no differ significantly (5).…”

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…Until now rFNA samples have been used for immunohistochemistry (27,28) and DNA-based analyses (29)(30)(31)(32)(33)(34), although feasibility of gene expression measurement has been explored (35). Considering the topographic heterogeneity in the breast, rFNA sampling is a useful tool for the discovery of breast cancer risk biomarkers; it provides a predominantly epithelial sample from a large area of the breast and allows the evaluation of women with clinically normal breasts, therefore greatly expanding the population for study, and eventual application of results.…”

BRCA1 affects global DNA methylation through regulation of DNMT1

“…It was recently shown that the overall frequency of CpG island promoter methylation is less abundant in BRCA1-associated breast cancers compared with sporadic cases [30,31]. These studies, which used quantitative multiplex methylationspecific PCR, were restricted to a dozen of genes (10 and 11, respectively) involved in breast carcinogenesis.…”

“…The pleiotropic effect of BRCA1 deficiency correlates well with the fact that BRCA1 interacts with many proteins with important functions, and that BRCA1 acts as a transcription factor, which regulates expression of many genes involved in many biological processes [28,29]. It was recently shown that methylation is less abundant in BRCA1-associated breast cancers compared with sporadic cases [30,31]. However, it is unclear if BRCA1 deficiency is directly related to this DNA hypomethylation, and whether BRCA1 affects expression of genes involved in DNA methylation, considering that global hypomethylation is a general hallmark of most cancer cells.…”